A Comprehensive Review on the Beneficial Roles of Vitamin D in Skin Health as a Bio-Functional Ingredient in Nutricosmetic, Cosmeceutical, and Cosmetic Applications

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The utilization and beneficial roles of vitamin D as a bioactive ingredient with applications in health-promoting functional cosmetics and skincare products, offering anti-inflammatory and anti-aging protection against psoriasis; dermatitis; acne; and other inflammation-related skin disorders.

Abstract

Vitamin D, also called the “sunshine” vitamin, has gained great attention recently due to the observed high percentage of the worldwide population being deficient in this essential bioactive vitamin. Primarily, vitamin D was known for its important role in bone health. Nevertheless, recent research has shown its importance for the brain, heart, muscles, immune system, and skin health, due to its distinct bio-functionality in almost every tissue in the human body. Therefore, its deficiency has been highly correlated with multiple diseases, including skin and dermatologically associated ones. Moreover, different methodologies are applied to synthesize vitamin D, while the main vitamin D sources in human plasma levels and the factors that can cause adverse modifications are multiple. Further research upon vitamin D has exhibited its notable role against skin diseases, such as psoriasis, atopic dermatitis, vitiligo, acne, and rosacea. In this article, a critical review of the most relevant and significant information regarding the relationship between vitamin D and skin health is thoroughly conducted, while emphasis is given to its potential uses and benefits in several cosmetic applications. Current status, limitations, and future perspectives of such a potent bioactive are also extensively discussed.

1. Introduction

Vitamin D’s history dates back to the 17th century when a rickets’ disease outbreak shocked and negatively impacted the global population [1,2]. In 1645, Daniel Whistler was the first to describe the term “Rickets”, known widely as the hallmark of vitamin D deficiency [2,3]. However, scientists for almost three centuries were not capable of acknowledging vitamin D’s potential as a significant protective, preventative, and therapeutic agent against this disease [4,5]. Kurt Huldschinsky proposed in the year of 1919 that ultraviolet B (UV_B) rays were sufficient enough to end the suffering and eventually heal rickets disease [6,7]. During the same year, dietary vitamin D deficiency was recognized as another factor by Sir Edwars Mellanby (1920), especially the deficiency of a vital component mostly traced in cod liver oil. In 1922, following the same scientific patterns, E. V. McCollum, after performing multiple animal studies over the years, managed to distinguish the several biological activities between the fat-soluble vitamins D and A, and ultimately, introduced the name “vitamin D” [8,9,10,11].

Despite the fact that vitamin D was deemed as an important compound for bone and calcium metabolism, its chemical structure was not yet uniformly established among scientists. Thereby, during the year of 1937, Windaus and Bock collaborated upon the chemical characterization of vitamins D₂ (ergocalciferol) and D₃ (cholecalciferol) [12,13,14]. More specifically, vitamin D₂ was laboratory-generated through the UV irradiation of the plant/yeast steroid ergosterol, while vitamin D₃ was formulated via UV irradiation exposure of 7-dehydrocholesterol. Interestingly, the newly emerged vitamin D₃ component was pointed out as the antirachitic constituent in cod liver oil [15]. Such notable findings marked the antirachitic vitamin D as a steroid, and more precisely a bioactive secosteroid. The year 1937 was when Nicolayson experimentally proved that vitamin D is essential for successful calcium (Ca²⁺) absorption, while 16 years later, it was also confirmed by this scientist that a low-calcium-based diet could increase Ca absorption [4].

The isolation of 25-hydroxy vitamin D₃ (25(OH)D₃) by DeLuca (1968) as well as the notable discovery of the vitamin D receptor (VDR) by Mark Haussler (1969) paved the way for the uncovering and chemical characterization of 1α,25-dihydroxy–vitamin D₃ (1α,25(OH)₂D₃; otherwise, calcitriol) by Hector DeLuca and Anthony Norman in 1971 [16,17,18]. Validated research findings demonstrated that 1α,25(OH)₂D₃ may interact with the VDR and modulate gene transcription in various cell types, an observation further supported by a scientific discovery regarding the human (as well as other) genomes, enabling gene regulation by 1α,25(OH)₂D₃ that generally impacts genes throughout the genome [19]. Adversely to DeLuca’s confirmation that the skin partakes in the synthesis of vitamin D in 1978, other researchers during this period associated vitamin D with multiple disease risks, a cause–effect relationship, globally addressed in many preclinical studies, clinical studies, and trials [20,21,22,23]. Historically, the “transcription era” marked the initial focus on vitamin D’s molecular and cellular mechanisms (1971–2000). This was followed by the “association era”, where researchers examined the link between vitamin D levels and various health outcomes (1980–2010). The “genomics era” emerged in the beginning of the 21st century (2000–present), emphasizing the exploration of genetic variations influencing vitamin D’s metabolism. Over the decades, clinical trials primarily centered on bone health and vitamin D’s role in preventing conditions like osteoporosis and rickets (1970–2010). More recently, the scientific focus has shifted to clinical trials investigating vitamin D’s non-skeletal effects, including its role modulating immune function, reducing inflammation, and managing chronic diseases and manifestations, such as cancer and cardiovascular disorders (Figure 1) [24].

Vitamin D is a naturally occurring, fat-soluble photoproduct found in both plants and human and animal skin. Vitamin D₂ is present in plants, while vitamin D₃ is traced mainly in the skin of humans and animals. The predominant difference between the two lies in the additional double bond in vitamin D₃ [25]. Both forms of vitamin D exhibit similar effects, and potency, and follow similar metabolic procedures [4]. Vitamin D is synthesized when exposed to UV_B radiation in fungi, plants, animal skin, and human skin. At this point, it is important to mention that other forms of vitamin D exist, such as D₁, D₄, and D₅, but are of little significance to humans [26]. Chemically, vitamin D shares a structure with cholesterol, consisting of four rings, labeled A, B, C, and D. A broken B ring in cholesterol results in the formation of vitamin D [24]. Since its discovery, vitamin D has been integrated into numerous applications, for several medical, cosmetic, and cosmeceutical purposes [10]. Furthermore, vitamin D has also been implicated in skin aging processes [27,28]. Many cells, particularly skin cells, can produce both vitamin D and its active form, which exerts distinct biological effects based on the target cell. This observation led to classifying vitamin D as a fat-soluble prohormone and its active form as a hormone [29]. The active complex of vitamin D₃, 1α,25(OH)₂D₃, plays a significant role as a regulator in a plethora of biochemical cascades and homeostasis systems [30].

The discovery of vitamin D’s astonishing properties sparked the development of a wide range of skincare products, cosmetic formulations, and systemic and topical analogs. Vitamin D’s anti-inflammatory [25,30], anti-melanoma [31,32], anti-cancer [33], anti-UV [25], anti-aging [25,27,34], and antioxidant properties [25,35] have been harnessed against various diseases or conditions, including psoriasis [36,37,38], atopic dermatitis [39,40,41], vitiligo [42,43], acne [44,45,46], and rosacea [47]. This review explores vitamin D’s structural, chemical, biological, and metabolic roles, highlighting its unique activity and supporting its increasing use in the cosmeceutical field. In addition, the review addresses vitamin D’s role in different skin-related conditions, the controversies surrounding its impact, and suggestions for future research mainly within the cosmetic domain. A timeline summarizing key milestones in vitamin D research is presented in Figure 1.

2. Methods

During requisite literature review, various databases were investigated including Scopus, Science Direct, MDPI, PubMed, and Google Scholar. The following broad combination of keywords was used, “vitamin D”, “cosmetics”, “applications”, “skin health”, “vitamin D₂”, “vitamin D₃”, “calcitriol”, “cholecalciferol”, “ergocalciferol”, “vitamin D deficiency”, “structure”, “calcium metabolism”, “bone metabolism”, “cosmetic formulations”, “topical analogues”, “skin cosmetics”, “conditions”, “skin disorders”, “acne”, “rosacea”, “atopic dermatitis”, “vitiligo”, “psoriasis”, “anti-inflammatory”, “anti-melanoma”, “antioxidant”, “anti-cancer”, “anti-UV”, and “anti-aging”, with the use of combinations of these keywords by using the AND and/or OR terms.

The research process was conducted during May–November 2024 regarding the last 5–7 years and the selection criteria and filtering features were established by delving into the available metadata from the pre-mentioned databases. This timeframe was chosen deliberately, with the aim of addressing the latest information on our topic and including recently published data, aligning with our main objective: pointing out the current knowledge status, presenting the latest research findings and comparing them to past ones, recognizing all existent limitations, and suggesting future ways to overcome them.

Each selected study was included due to following several pre-established criteria, such as being exclusively research-based articles, including eligible reviews and clinical trials from the aforementioned valid scientific databases. Moreover, all research articles must have been written in the peer-reviewed English language. Additionally, all included publications should have been published between 2018 and 2024. At this point, it must be pointed out that a few important articles published prior to the year of 2018, but followed the inclusion criteria and enclosed important data that were not mentioned in more recent paper reviews, were as well included in our study. If a research paper was in accordance with the above criteria, with a view to evaluate the quality and relevance of each included article, all articles were then thoroughly assessed concerning their title, abstract, and keywords utilized. Subsequently, all remaining articles were extensively analyzed in order to confirm whether they met all predefined inclusion criteria and incorporated relevant information for our review. This article cites predominantly valid academic papers, press releases from research institutes and universities, authentic clinical trials, observational studies, meta-analyses, experimental-founded studies, and well-grounded scientific reviews and peer-reviewed papers. All extracted data were synthesized collectively by all authors, and all conflicting findings were addressed collaboratively. Zotero 6.0.36 software was also utilized for citing the selected publications.

Articles retrieved from non-well-founded databases or unrelated to the topic were excluded along with duplicates or publications written in other languages rather than the English one. Conference papers, book chapters, government publications, theses, dissertations, technical reports, working papers, non-academic reports, internal documents, presentations, white papers, websites, newsletters, short surveys, previous publications, old reviews, newspaper or magazine articles, blog articles, open-content resources, and otherwise collaborative knowledge databases (e.g., Wikipedia) were also excluded. Articles with a low relevance score, very few citations, or a low impact factor and papers with methodological flaws and high bias, were excluded and deemed as the “gray literature” (Figure 2).

3. Vitamin D’s Structural Profile, Skincare Applications, and Functions

3.1. Chemical Structure and Types of Vitamin D

Vitamin D refers to a group of fat-soluble secosteroids essential for various bodily functions. Particularly, vitamin D plays an important role in calcium and phosphorus metabolism, which is crucial for maintaining bone health. The two primary forms of vitamin D are vitamin D₂ (C₂₈H₄₄O) and vitamin D₃ (C₂₇H₄₄O) (Figure 3). Both forms derive from different sources, and their own individual chemical structures, and exhibit distinct biological activities, as vitamin D₂ is present in plants and yeast while vitamin D₃ derives from animal sources. Vitamin D’s chemical structure is mainly depicted as a steroid molecule. Sex hormones, adrenal hormones, and cholesterol are placed amongst the many chemical molecules that make up the huge family known as steroids. Interestingly, a unique feature of vitamin D’s structure is its secosteroid nucleus, which resembles a steroid nucleus but lacks one of its rings. Four rings designated as A, B, C, and D make up the secosteroid nucleus as important components of the cyclopentanoperhydrophenanthrene skeleton. The B ring especially is broken at the 9, 10 carbon–carbon bond with a view to form pre-vitamin D. Small differences comprise the molecular structures of vitamin D₂ and D₃. Specifically, the methyl group at carbon 24 and a double bond located between carbons 22 and 23 are present in vitamin D₂. In comparison to vitamin D₃, the methyl group at carbon 24 is absent and only one bond is found between carbon 22 and 23. These structural variations are primarily responsible for their stability and metabolism within the human body and impact the sequence of many biochemical processes [48,49]. The two primary forms of vitamin D are depicted in Figure 3 and Figure 4.

Sunlight is the most significant and natural source of vitamin D. Sunlight’s UV_B rays cause the skin’s 7-dehydrocholesterol to automatically transform into provitamin D₃, which subsequently changes into vitamin D₃. Latitude, season, time of day, skin pigmentation, age, and usage of sunscreen are only a few of the variables that might affect the skin’s ability to produce vitamin D₃ [50]. In the case of vitamin D₂, the main sources of vitamin D₂ are fungus and plants formed by subjecting ergosterol—a sterol present in plant and fungal cell membranes—to ultraviolet radiation [51]. As vitamin D₃ reaches the liver, it is converted by the aid of enzymes to 25(OH)D₃. 25(OH)D₃ is then transformed to 1α,25(OH)₂D₃ in the kidneys, and this process will be explained in more detail in the following section (Figure 2) [30]. Vitamin D₃ is also present in animal-based foods like fatty fish (salmon, mackerel, and sardines), cod liver oil, egg yolks, and fortified dairy products (20%). For those at risk of deficiency, and especially people dealing with limited sun exposure, older adults, and those with specific medical problems that influence their metabolism of vitamin D, vitamin D supplements are vital (Figure 3) [52].

3.2. Absorption of Vitamin D from Skincare Products

Vitamin D is incorporated in skincare products offering a wide range of beneficial effects. However, it is important to note that topical vitamin D application does not replace the need for its systematic consumption, which is essential for overall health. Vitamin D₃ is more frequently incorporated in skincare formulations, improving the appearance of fine lines and wrinkles, decreasing inflammation, and enhancing skin moisture. During the winter, when skin is typically drier and more prone to irritation, skincare products with vitamin D₃ are quite helpful. Different skincare formulas enable personalized routines that target certain requirements. These products focus on key goals such as improving skin hydration, reducing inflammation, and enhancing overall skin health by promoting and providing better texture, tone, and resilience [53].

Calcipotriol, also known as calcipotriene, is commercially available in several products under the brand names Dovonex^® and Diavonex^®, with comparable efficacy reported to that of calcitriol, due to its identical affinity for VDRs. Calcipotriol has significant impact on the immunosuppression of inflammatory mediators and melanin formation enhancement [54]. Multi-hyaluronic antioxidant hydration serums [55], multivitamin supplies including vitamin D [56], vitamin D₃ orally administered coating tablets [57,58], oral capsules [59], softgel formulations [60], topical calcineurin [61], cosmetic serums destined for facial skin improvement [62], and vitamin D₃–phytochemical complex formulations [63] have been clinically approved and utilized in several acne, vitiligo, atopic dermatitis, psoriasis, rosacea, and anti-aging treatment strategies globally, and have offered multiple beneficial outcomes.

Vitamin D as a natural photoproduct that is mainly administrated either as an oral supplement (e.g., tablet, syrup, soft gel capsules, and other supplements) or in an injectable dosage form is connected with many beneficial outcomes for the body [25,64]. Nanotechnology has revolutionized medicine by encouraging targeted cellular drug delivery, enhancing the bioavailability of encapsulated vitamin D and its derivatives, and promoting several health-associated benefits. Organic, and especially lipid-based, nanocarriers for the delivery of vitamin D and its analogs have been extensively utilized over the past few years, stabilizing this hormone, improving its solubility, enhancing its absorption, and enabling and bettering targeted cellular release in specific tissues. Such innovative systems have overcome several adverse effects of oral administration including poor permeability in epithelial barriers and solubility [65]. Furthermore, photodynamic therapy supplemented with vitamin D₃ has increased 6–30% of the response of this treatment against squamous cell carcinomas (SCCs), actinic keratosis, and psoriasis, in a plethora of breast cancer cell lines and animal models [66]. For instance, topical vitamin D formulations enhanced with cholecalciferol, calcipotriol, or tacalcitol have been confirmed to stimulate melanin and melanogenesis during narrowband UV phototherapy (NB-UV_B), in therapeutic treatments against vitiligo [54,67]. However, in conjunction with psoralen long-wave UV radiation (PUVA) and monochromatic excimer light (MEL) vitiligo treatments, less beneficial effects have been recorded, in contrast to vitamin D combined with corticosteroid formulations, where vitamin D minimizes the adverse impact of corticosteroids and offers superior efficacy and vitamin D microneedle provision [54,68,69].

Interestingly, recent study outcomes confirmed that tumor cells of various origins are capable of expressing VDRs and enabling restrained growth and cancer cell arrest/apoptosis. An optimized vitamin D₃ nanospray formula had fewer drips, fast drying time, and long-term storage capacity, and maintained bioavailability and biological stability, as well as a faster coverage of the administration time, in less delivery time and enhanced efficacy [70]. Finally, a recent clinical trial revealed that vitamin D supplementation was interconnected with a notable chronic pruritus severity reduction, as well as a decrease in the skin lesion area, and inflammatory cytokine levels including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP) [71]. Furthermore, carboxymethyl-cellulose-based hydrogels integrated with cellulose nanocrystals loaded with vitamin D have been pointed out as great vitamin D carriers for controlled and targeted drug delivery, mainly in cases of vitamin D deficiency [72].

The absorption of vitamin D in the skin entails different biochemical processes such as penetration through the stratum corneum, diffusion through the epidermis, and interaction with keratinocytes, which lead to the activation of the vitamin D form. The initial part of vitamin D absorption in skin is its penetration through the stratum corneum—the skin’s outermost layer. This layer functions as a barrier to various substances and is made up of dead keratinocytes embedded in a lipid matrix. Vitamin D’s lipophilicity facilitates its pass through this layer’s lipid matrix. Moreover, the product’s formulation can increase skin permeability through this lipid matrix, by containing suitable ingredients [53].

The second step of the absorption process is vitamin D diffusion via the viable epidermis where the viable keratinocytes have a significant role in metabolizing and utilizing vitamin D. Vitamin D interacts with keratinocytes once it has penetrated the epidermis, while the nuclear VDR that mediates the biological effects of vitamin D is also present. Vitamin D binds to the VDR, leading to its activation, a situation that allows the VDR to control and mediate the production of genes related to immunological responses, cell division, and proliferation, effectively [73].

The keratinocytes, the main cells found in the epidermis, act as enzymatic machinery converting vitamin D from its inactive to its active form. For instance, keratinocytes are capable of transforming vitamin D₃ into 1α,25(OH)₂D₃, its active metabolite, which is essential for vitamin D₃’s skin regulatory actions [73,74]. Consequently, various biological incidences arise from the activation of VDR in keratinocytes, including immune response regulation that reportedly lowers inflammation and promotes wound healing, and cell differentiation stimulation, responsible for fortifying the skin barrier [73,74].

3.3. Topical Vitamin D Analogs

Calcitriol (1α,25(OH)₂D₃) is widely recognized as the active form of vitamin D, which is essential for skin cell differentiation, the inhibition of proliferation, and local immunomodulation [75]. In 1985, after using oral vitamin D₃ supplements, a patient with severe psoriasis and osteoporosis symptoms displayed remarkable improvement [76]. However, in the following ten years, an interactive bridge between vitamin D₃ supplementation and psoriasis was unfortunately not achieved. Furthermore, managing occurring side effects such as nephrocalcinosis, nephrolithiasis, hypercalcemia, hypercalciuria, and decreased bone mineral density became an extremely difficult task for the scientific community [77]. Nonetheless, such pitfalls urged the investigation of vitamin D substitutes with the aim to prevent all negative consequences. As a consequence, topical calcipotriene (calcipotriol) foam was approved by the US Food and Drug Administration in 1993 for the treatment of mild-to-moderate psoriasis. Additionally, more than 15 years later, a topical 1α,25(OH)₂D₃ ointment was approved for mild-to-moderate psoriasis treatment. Since then, topical vitamin D analogs—either alone or in conjunction with topical corticosteroids—have become a crucial component in psoriasis treatment strategies. These vitamin D analogs are currently commonly integrated in topical therapeutic interventions, minimizing the reliance on steroid use [78,79,80].

Topical vitamin D analogs directly provide a convenient, safe, and generally well-tolerated therapeutic alternative and examples of such therapeutic means are depicted in

Table 1. Anti-Melanoma, Anti-cancer, and Anti-UV Activities of Vitamin D.

Study Hypothesis	Cosmetic Application	Main Activity	Pathway	Results	Reference
This study demonstrated the effects of secosteroidal analogs (1α,25(OH)2D3 and 25(OH)D3) and non-calcemic ones (20(OH)D3, calcipotriol, 21(OH)pD, pD, and 20(OH)pL) on proliferation, colony formation in both monolayer and soft agar, and mRNA and protein expression by melanoma cells	In vivo testing	Anti-melanoma	In primary cultures of Ab cells freshly isolated from solid tumors, moderate-melanin-pigmentation sensitized cells towards 1α,25(OH)2D3, 25(OH)D3, and the short side-chained 21(OH)pD analog were prepared Moreover, two rodent (mouse and hamster) melanoma models were used Inhibitory effects of vitamin D and lumisterol analogs were tested with a short side-chain, including pD, 20(OH)pL, and 20(OH)pD, on a colony in soft agar The testing was performed on primary cell cultures using melanoma cells, isolated from transplantable Ab amelanotic tumors Murine B16-f10 and hamster Bomirski Ab cell lines were utilized as models to study the effect of melanin pigmentation and its influence in the expression of genes The last Western blot was performed to show the VDR synthesis as well as its translocation to the nucleus	Only 21(OH)pD showed antiproliferative effects All three lumisterol analogs having side-chain pD, 20(OH)pL, and 20(OH)pD inhibited colony formation in soft agar 1α,25(OH)2D3 decreased the ability of primary Ab cells to form colonies in soft agar assays, following also a dose-dependent manner and resulting in decreased size Pigmentation increased the expression of VDR and co-receptors like the retinoid X receptor (RXR) at the mRNA level 1α,25(OH)2D3 treatment increased the VDR and CYP24A1 mRNA levels in pigmented Ab cells compared to in the non-pigmented ones The Western blot analysis showed the stimulation of the VDR translocation by 1α,25(OH)2D3	[82]
An investigation of the role of RXRα and its partners in mouse skin tumor formation and malignant progression upon topical mutagen dimethylbenzanthracene (DMBA)/12–O–tetradecanoyl phorbol–13–acetate (TPA) treatment was followed in this study	In vivo testing	Anti-cancer, anti-melanoma	The two-step chemical tumorigenesis model was used to study the 3 different stages, namely the initiation, promotion, and progression of mouse skin-originated tumors Human squamous cell carcinoma (SCC) acts similarly to mouse chemically activated squamous cell tumors The initiation takes place after a single topical application of DMBA. Promotion is achieved by a repeated topical application of a tumor promoter (i.e., terephthalic acid (TPA)) The application of a tumor promoter results in sustained hyperplasia and inflammation and then in a benign papilloma The last stage is the progression where a conversion of the benign papilloma to invasive SCC occurs	Keratolytic RXRα has a key role in the formation and malignant transformation of DMBA/TPA-induced epidermal skin tumors	[83]
An examination of the role of the active forms of vitamin D in regulating the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activity in melanoma cells that are dependent on melanin	In vitro testing	Anti-melanoma	Firstly, an examination of the induction of melanin pigmentation was performed to check if it can affect the VDR expression Secondly, in order to test the subcellular location of the p65 NF-κB subunit in SKMEL-188 melanoma cells, the preparation of cytoplasmic and nuclear extracts with pigmented and non-pigmented melanoma cells took place The further characterization of the activation of the NF-κB in melanoma cells required an immunofluorescent staining performance for p65 in both pigmented and non-pigmented SKMEL-188 cells To determine which 20(OH)D3 or 1α,25(OH)2D3 affected NF-κB-driven transcriptional activity, pigmented and non-pigmented melanoma cells were transfected with a NF-κB-dependent luciferase reporter construct (NF-κB-p-Luc) An electrophoretic mobility shift assay (EMSA) was used for the determination of the NF-κB DNA-binding activity by using an NF-κB oligonucleotide probe An enzyme-linked immunosorbent assay (ELISA), a Western blot, and immunofluorescence were utilized so as to characterize in more detail the effect of secosteroids and the pigmentation of NF-κB activity and especially to examine p65 nuclear translocation An analysis of biopsies of human melanoma cells was used to examine the reflection of their pigmentation	An inversely proportional relationship was found between the melanin content and the VDR protein expression The analysis of the Western blot showed that in non-pigmented SKMEL-188 melanoma cells, a higher nuclear level of p65 was indeed traced Intense p65 nuclear staining was concluded to be present in non-pigmented melanoma cells On the other hand, in the pigmented ones, p65 was shown to be localized mainly in the cells’ cytoplasm Both secosteroids, 20(OH)D3 and 1α,25(OH)2D3, were shown to reduce the NF-κB-driven transcriptional activity in non-pigmented melanoma cells in a time-dependent mechanism of action Nuclear extracts prepared by non-pigmented SKMEL-188 melanoma cells showed a higher activation of NF-κB DNA-binding activity, compared to extracts prepared by pigmented cells Treatment of non-pigmented cells with 20(OH)D3 resulted in a time-dependent inhibition of NF-κB-dependent DNA-binding activity, versus treatment of pigmented cells that had no effects on the NF-κB activation When non-pigmented SKMEL-188 melanoma cells were treated with 20(OH)D3, the nuclear levels of p65 were decreased and the cytoplasmic levels increased, subsequently When pigmented cells were treated either with 20(OH)D3 or with 1α,25(OH)2D3 intracellularly, the localization of p65 was not affected at all. Especially, p65 was mainly found in the nucleus of non-pigmented cells In human biopsies, the results showed that pigmentation affects the activity of NF-κB as the intracellular distribution of p65 changes Therefore, higher nuclear p65 levels were traced in non-pigmented than in pigmented melanoma cells	[84]
An investigation of skin cancer therapy in mouse models of skin carcinogenesis with the application of topical calcipotriol was conducted. An additional randomized, double-blind clinical trial investigation for testing the combination of 0.005% calcipotriol ointment together with 5% fluorouracil (5-FU) cream and its comparison with Vaseline and 5-FU used in the treatment of actinic keratoses on the face, scalp, and upper extremities was tested as well	In vivo and in vitro testing	Anti-cancer	First, calcipotriol was applied three times per week at the mouse’s skin-located carcinogenic site, so as to test the induction of the thymic stromal lymphopoietin (TSLP) in the skin Secondly, the impact of short-term TSLP induction by calcipotriol was tested As an experimental example, calcipotriol was used as a short pulse and in the starting stage of the tumor, in DMBA-TPA-treated animals Calcipotriol was applied to the ears, every day for 3 days in a row In order to test the human approach regarding the efficacy of TSLP induction as a cancer immunotherapeutic candidate, a hypothesis of a combination of calcipotriol and 5-FU was made 5-FU used alone follows the recommended use of twice daily, for 2–4 weeks. This randomized, double-blind, clinical trial took place to examine the results after using a combination of 0.005% calcipotriol ointment (final concentration: 0.0025%) combined with 5% 5-FU cream (final concentration: 2.5%) twice, for 4 days	Topical calcipotriol blocked skin cancer via the TSLP expression in the skin Increased serum levels of TSLP were the result of treatment with a short calcipotriol regimen, which led to a long-lasting anti-cancer effect, highlighting the effectiveness and the safety of this topical agent The synergistic effect of calcipotriol and 5-FU was further supported due to an observed activation of the CD4+ T cell-mediated immunity cells and the subsequent protection against actinic keratoses and potential skin cancer onset	[85]
An investigation regarding the ability of novel non-calcemic secosteroids on how they could protect against solar radiation, which can damage human epidermal keratinocytes, melanocytes, and HaCaT keratinocytes, was conducted in this study	In vitro	Anti-melanoma	CYP11A1, including epidermal keratinocytes, can metabolize vitamin D3 and produce 20S(OH)D3 as the major metabolite and 20,23(OH)2D3 as the second major metabolite of the pathway Smaller quantities of other mono-, di-, and tri-hydroxy-derivatives of vitamin D3 may also be produced The first step was the confirmation that HaCaT keratinocytes can generate 20S(OH)D3 from vitamin D3 precursors, showing in this way that 20S(OH)D3 is present in the human epidermis in vivo After that, a test regarding the protective effects of non-calcemic 20S(OH)D3 and 20,23(OH)2D3 against UVB-induced damage in comparison to 1α,25 (OH)2D3 and related sterols, in human epidermal keratinocytes and melanocytes, took place A preliminary experiment followed, where the MTS test on HaCaT keratinocytes was held so as to make a comparison between the protective effects of 20S(OH)D3, its enantiomer 20R(OH)D3, and precursors 20S(OH)7DHC and D3 against UVB-induced cell death To continue, 20S(OH)D3 and 20,23(OH)2D3, in comparison to 1α,25(OH)2D3, 20S(OH)7DHC, 7-hydroxycholestrol (7(OH)C), and cholesterol sulfate, were tested in order to check if they could weaken ROS production, followed by UVB exposure A following test was conducted so as to check if vitamin D hydroxy-derivatives and 20S(OH)7DHC can scavenge H2O2, which was formed as a direct response to UVR An additional test was also held so as to confirm the protective effects of 20S(OH)D3 on the UVB-induced production of nitric oxide (NO) The effects of 20S(OH)D3, 20,23(OH)2D3, 20S(OH)7DHC, 1α,25(OH)2D3, and 25(OH)D3 on the relative glutathione (GSH) content were tested as well An investigation on whether secosteroids can stimulate the expression of genes was additionally conducted A final experiment that was held and was utilized to analyze the DNA damage was the Comet assay, where a visualization of the DNA migration was performed by fluorescence microscopy	20S(OH)D3 could speed up the cell death induced by UVB The preliminary experiment showed that only 20S(OH)D3 could weaken the cell death, which was induced from UVB Also, they reported that the R enantiomer had a smaller potency compared to the S enantiomer Therefore, the S enantiomer, the naturally occurring one, was selected for further experiments All hydroxy-derivatives of vitamin D3, except for 7(OH)C and cholesterol sulfate, as well as 20S(OH) 7DHC, could help reduce the UVB-induced ROS production When cells were treated with 20S(OH)D3, 20,23(OH)2D3, 20S(OH)7DHC, 1α,25(OH)2D3, or 25(OH)D3, there was a significant reduction in H2O2 in concentration after UVB exposure Treatment of cells with 20S(OH)D3, 20,23(OH)2D3, 20S(OH)7DHC, 1α,25(OH)2D3, or 25(OH)D3 before UVB irradiation reduced NO production. Specifically, 20(OH)D3, 20,23(OH)2D3, 1α,25(OH)2D3, and 20(OH)7DHC strongly inhibited the NO generation A significant reduction in the GSH content was observed as an aftermath of UVB exposure Extensive DNA damage was observed, after the exposure of melanocytes to UVB radiation, while 20S(OH)D3, 20,23(OH)2D3, and 1α,25(OH)2D3 were found to be the most protective agents against UVB-induced damage	[86]

[81]. Although exclusively authorized for psoriasis, they have demonstrated effectiveness in treating numerous other dermatological conditions [81].

3.4. Indicative Beneficial and Adverse Functions of Vitamin D in the Human Body

Vitamin D plays a pivotal role in maintaining calcium and phosphorus homeostasis, which is essential for bone mineralization. It promotes the absorption of calcium and phosphorus from the gut, reabsorption of calcium in the kidneys, and mobilization of calcium from bones. These actions ensure adequate levels of calcium and phosphorus for the formation and maintenance of healthy bones and teeth. As widely supported, a deficiency in vitamin D might lead to bone disorders such as rickets in children and osteomalacia in adults, characterized by soft and weak bones [87]. Hence, vitamin D-based treatment is believed to reduce inflammation and boost the ability of monocytes and macrophages, two types of white blood cells (leukocytes), vital to the immune defense and responsible for combating pathogens. By controlling the synthesis of antimicrobial peptides and adjusting immune cell activity, vitamin D contributes to the prevention and management of infections and autoimmune disorders [50]. Moreover, it has been demonstrated to control cell division and proliferation, and prevent specific malignancies’ spread by interfering with cancerous cells’ proliferation and induction of their differentiation [88]. Vitamin D’s role mainly lies in controlling cell growth, but also acting as a defense mechanism, by balancing the skin’s high rate of cell turnover [50].

Vitamin D₃ and its receptor (VDR) are ultimately crucial in maintaining skin health [89]. Primarily, it is essential for the proper functioning and integrity of the skin barrier [90]. By facilitating the differentiation of keratinocytes, namely skin cells that basically form the outermost layer, vitamin D aids in maintaining a robust epidermal barrier able to protect an organism against infections and environmental damage [91,92]. Additionally, vitamin D modulates cell growth and differentiation, a vital function in conditions characterized by abnormal cell proliferation, such as psoriasis or even skin cancer, and also supports wound healing, by promoting cell repair and regeneration [21,93,94]. Moreover, this hormone exhibits its anti-inflammatory profile, by reducing inflammation and contributing to managing conditions like eczema [95,96]. Overall, vitamin D’s impact on the skin’s health underscores its importance in maintaining skin barrier function, regulating cell growth, and enhancing the skin’s natural defense mechanisms [87].

However, apart from vitamin D’s beneficial impact, some adverse effects do exist but can be easily managed. Hypervitaminosis D results from excessive intake of vitamin D supplements, leading to elevated serum calcium levels (hypercalcemia) and associated complications [97]. Pointedly, high 1α,25(OH)₂D₃ increases intestinal calcium absorption; thus, elevated calcium and phosphate levels may induce the supersaturation of urine, promoting the formation of calcium oxalate or calcium phosphate crystals, the primary components of renal calculi (kidney stones). Prolonged hypercalcemia can unfortunately lead to nephrocalcinosis, a condition marked by calcium deposition in renal tissue, impairing kidney function [97,98,99,100,101]. Moreover, such a vitamin D increase and regulation failure for individuals poses several risk factors for individuals with predisposing conditions including chronic kidney disease (CKD), hyperparathyroidism, or sarcoidosis [102,103,104]. In CKD especially, impaired kidney function reduces the conversion of 25(OH)D₃ to its active form, often requiring supplementation. Over-supplementation may adversely worsen hyperphosphatemia and accelerate vascular calcification, increasing the risk of CVD complications, while high vitamin D doses may also suppress the parathyroid hormone (PTH), leading to adynamic bone disease [30,103,104]. Moreover, in autoimmune disorders like sarcoidosis or tuberculosis, macrophages may autonomously produce 1α,25(OH)₂D₃, independent of PTH regulation, where in such cases, vitamin D supplementation may exacerbate hypercalcemia and its complications [102,105].

Hyper-elevated levels of vitamin D have additionally many other negative influences in several chronic diseases. For instance, hypercalcemia-induced vascular classification initiated by excess vitamin D may contribute to calcium deposition in arteries, leading to arterial stiffness, hypertension, risk of arrythmias, and several other cardiovascular-associated disorders (CVDs) [22,106]. Some studies also suggest that excessive vitamin D may contribute to certain cancers’ progression, such as prostate cancer, although evidence is mixed. Over-vitamin D supplementation could disrupt cellular signaling pathways involved in apoptosis and proliferation [107]. In addition to the previous complications, chronic hypervitaminosis may lead to bone resorption, because of increased PTH suppression and osteosclerosis (excessive bone hardening) or brittleness, from dysregulated calcium homeostasis [108,109,110]. Finally, some negative, hypercalcemia-related neurological symptoms like confusion, lethargy, and in severe cases such as comas have been recorded, but research is still required for fully comprehending this association [97,111].

4. Skin Biology, Vitamin D Synthesis, and Its Impacting Factors

4.1. General Structure and Function of Skin

The largest space-consuming organ in the human body is the skin, which has an average surface area of 2 m² in humans and is the body’s main line of defense against harmful substances, ultraviolet light, microbes, and physical trauma. It acts as a complex barrier and interfaces between the internal and external environment of the body. In addition, it serves as an excretory, sensory, and immunologically active organ and partakes in the regulation of the body’s temperature [112]. The epidermis, dermis, and hypodermis are namely the three main layers that make up the skin [113]. The outermost layer, known as the epidermis, is made up of a stratified squamous epithelium that is mostly composed of keratinocytes [114]. Layers of keratinocytes move from the stratum basale to the stratum corneum, where they mature into corneocytes and eventually shed to form the epidermis that performs various barrier functions [113,115]. Corneocytes in the stratum corneum then are enclosed in a lipid matrix that resists shearing forces and permits water loss, functioning as a “bricks and mortar” system. In the stratum corneum, lipids produced by lamellar bodies constitute a vital barrier, controlled by calcium concentrations [112]. At this point, it must be referred to that fibroblasts inside a collagen–elastin matrix, blood arteries, lymphatic vessels, nerve terminals, and skin appendages like hair follicles and glands are all located in the dermis, a connective tissue layer that lies underneath the epidermis. Adipose tissue, which fabricates the hypodermis, serves as insulation, a cushioning agent, and the starting point for blood arteries that continue into the dermis [114].

Many vital tasks necessary for preserving health and homeostasis are carried out by the skin [116]. In addition to reducing water loss and preserving hydration, skin serves as a barrier of defense, protecting internal organs from environmental danger such as infections, toxins, and physical damage [117,118,119]. By producing perspiration and modifying blood flow, the skin plays a crucial part in thermoregulation [120]. Being a sensitive organ, it has receptors for pain, pressure, touch, and temperature changes, all of which enable one’s body to react to outside stimuli. Another essential role of the skin involves, among many other immune responses, the one due to Langerhans cells that constitute the immunological defense, deciphering skin’s ability to recognize and counteract infections. Furthermore, exposure to UV_B rays stimulates the skin to synthesize vitamin D, necessary for bone health and calcium absorption, while the skin aids in the excretion of body wastes such as salts and urea through its appendages, the sweat glands. Such distinct roles demonstrate how important the skin is as a dynamic, multipurpose organ for defense, control, and general physiological homeostasis [115].

4.2. Synthesis and Metabolism of Vitamin D in Human Skin

Pre-vitamin D₃ is created via a photochemical reaction involving provitamin D₃, also known as 7-dehydrocholestrol (7-DHC), which is a precursor mostly present in the basal and spinous cell layers of the skin’s epidermis [121]. More specific to this is the stratum basale, comprising stem and transient amplifying cells that generate the upper cells, which in turn produce keratins K5 and K15 and proliferation markers such as β-catenin (CTNNB), cyclin D1, and the GLI1 gene. After migrating to the spinous layer, the cells produce different keratins, namely K1 and K10, as well as enzymes and precursors implicated in cornified envelope formation, namely involucrin and transglutaminase-K. Filaggrin and loricrin protein expressions mark the beginning of further migration into the stratum granulosum, thus contributing to cornified envelope generation. Such cells additionally partake in lipid production, including lipids packaged into lamellar bodies, and are injected into the intracellular spaces between the stratum granulosum and stratum corneum with a view to waterproof the permeability barrier. Interestingly, lamellar bodies contain antimicrobial peptides like cathelicidin formulated in the stratum granulosum, providing protection against invasive organisms. VDR and CYP27B1 expression is the highest in the stratum basale, where the mediator of RNA polymerase (MED1) and the steroid receptor coactivator-3 (SRC-3) are two major VDR action coregulators. On the one hand, MED1 expressed mainly in the stratum basale and spinosum facilitates VDR’s modulation of proliferation at early stages of differentiation, and stratum granulosum SRC-3 accelerates the VDR’s regulation of terminal differentiation [122].

Along with its effects on the kidneys, calcitriol bound to the vitamin D binding protein also affects target organs that express VDRs, such as the bone, gut, and parathyroid (PTH) gland, via both genomic and non-genomic pathways. Geographical, seasonal, and environmental factors including pollution, sun exposure, month, location, or altitude heavily affect the amount of vitamin D generated and the time required for this procedure [123]. Under the predominant impact of UV_B radiation (280–320 nm), 7-DHC is quickly converted to pre-vitamin D₃ (pre-D₃) in the skin, and then pre-D₃ rearranges under heat (thermal) exposure to generate vitamin D₃. By converting pre-D₃ into the physiologically inert substances tachysterol and lumisterol through continued UV_B exposure, harmful D₃ buildup is avoided. Lumisterol and tachysterol are reverted back to pre-D₃ in dark conditions (Figure 5) [30]. Thus, skin pigmentation and UV intensity impact this process; melanin absorbs UV radiation, lowering the efficiency of D₃ generation in people with darker skin, which helps explain why these target groups demonstrate lower 25(OH)D₃ levels in clinical tests [124]. At the end of this procedure, vitamin D₃ enters the bloodstream and is transported to the liver, after binding to the VDR [30,121].

Skin pigmentation is influenced by the melanin pigment, as well as seasonal aspects, UV_R’s impact, tanning, and genetic adaptation capabilities. Direct skin sun exposure to sun rays and the need to improve thermoregulation also led humans to gradually evolve the skin pigment over time. Interestingly, skin pigmentation not only acts as a shield against UV_R damage, but also as an important defensive mechanism against heat dissipation and vitamin D deficiency, and thus, an evolutionary balancing aspect between vitamin D synthesis, vitamin D’s activities, and UV_R protection [125].

Seasonal differences may also have an impact on D₃ production in areas far from the equator; vitamin D₃ levels affected by melanin’s activity are higher during summer, and lower during winter levels. Furthermore, younger age, darker skin type, not using vitamin D supplementation, not consuming oily fish, and living in specific low-UV regions are all predicting factors of vitamin D deficiency, poor myoskeletal health, and chronic health issues [126]. Such observation comes in accordance with research studies highlighting that the risk of rickets and osteomalacia is higher in completely clothed Bedouin people under similar sunshine conditions than in less covered cultures, suggesting that clothing based either on personal preferences or religious practices and sunscreens may limit D₃ production. Conflicting studies, however, proved that the use of sunscreen during summer allows sufficient sunlight to be received, enables vitamin D, and does not interfere with vitamin D deficiency [127,128]. The skin produces vitamin D₃ in a safe and controlled manner thanks to photoconversion procedures and environmental influences [129]. Of note, ozone has an excellent function in mitigating hazardous UV_C rays that pass through the stratosphere, and hence, preserves skin health [130].

Following its production, the metabolism of vitamin D₃ is a procedure first conducted in the liver and then in the kidneys. Vitamins deriving especially from food bind to the VDR, with this complex reaching the liver and being converted to 25(OH)D₃. This compound, as it reaches the kidney, is then enzymatically converted by 25(OH)D₃-1α-hydroxylase (CYP27B1) and several other cofactors like nicotinamide adenine dinucleotide phosphate (NADPH), magnesium, and interaction with other degrading enzymes of vitamin D metabolites, like CYP3A4, to two distinct bioactives. More specifically, through a hydroxylation in the 1α (A ring) position, 25(OH)D₃ is converted to 1α,25(OH)₂D₃ and through the hydroxylation in the 24th position, 25(OH)D₃ is directly converted to 24,25-dihydroxyvitamin D₃ (24,25(OH)₂D₃). The first conversion leads to increased PTH and fibroblast growth factor-23 (FGF-23) levels and decreased phosphorus (P) (phosphate excretion by the kidneys) and Ca levels (calcium resorption from bones), while the second conversion, in contrast, leads to elevated P and Ca (due to renal reabsorption of phosphate) levels (Figure 5) [30]. Ultimately, 1α,25(OH)₂D₃ promotes calcium and phosphate absorption, while 24,25(OH)₂D₃ inhibits excessive Ca absorption, preserving balance [30].

However, excessive 1α,25(OH)₂D₃ may lead to conditions like hypercalcemia and hyperphosphatemia, contributing to complications such as vascular classification, skeletal anomalies, and renal calculi [131,132]. Furthermore, in CKD patients, impaired 1α-hydrolase activity results in decreased 1α,25(OH)₂D₃ levels, leading to secondary hyperparathyroidism and bone mineral disorders [30,103]. On this note, a deficiency in 25-hydroxylase, otherwise CYP2R1 deficiency, induces vitamin D-dependent rickets type 1B [133,134]; CYP27B1 mutations are associated with vitamin D-dependent rickets type 1A [133,135], and polymorphisms in CYP24A1 may cause hypercalcemia [133,136].

Besides producing vitamin D₃, keratinocytes also convert it into its active form, 1α,25(OH)₂D₃, through the enzymes vitamin D-25 hydroxylase CYP27A and CYP27B1. Unlike most cells, which rely on the kidneys for circulating 1α,25(OH)₂D₃, keratinocytes are able to operate this entire mechanism to perform this conversion. Higher quantities of CYP27B1 are expressed by keratinocytes than by kidney cells, further suggesting that the skin produces 1α,25(OH)₂D₃ primarily for local application rather than systemic circulation. Such local production enhances innate immunity, increasing the expression of antimicrobial peptides like cathelicidin, and modulates the adaptive immune system, promoting T cells and reducing inflammation activity. This local activation occurs even under conditions where circulating levels of 1α,25(OH)₂D₃ might be low due to impaired kidney function such as in CKD [30,103]. Via a different mechanism than the one in the kidney, the PTH promotes the creation of 1α,25(OH)₂D₃ in keratinocytes, since they do not respond to cycle adenosine monophosphate (cAMP) and do not own the PTH receptor. This makes keratinocyte-driven 1α,25(OH)₂D₃ generation independent of systemic PTH control, highlighting a local, rather than a systemic, role and a preventative effect against hyperproliferating conditions like psoriasis [129].

Additionally, 1α,25(OH)₂D₃ regulates its own levels within keratinocytes by inducing 25(OH)D₃-24-hydroxylase (CYP24A), which breaks down 1α,25(OH)₂D₃ and prevents excess levels. This feedback mechanism ensures that little 1α,25(OH)₂D₃ enters the bloodstream from the skin. The activity of CYP27B1 in keratinocytes varies according to their differentiation and is the highest in undifferentiated cells and in the stratum basale of the epidermis. Elevations in factors like TNF-α and interferon-gamma (IFN-γ), in conditions like eczema and psoriasis, enhance 1α,25(OH)₂D₃ production in response to UV light and skin barrier disruption, increasing CYP27B1 expression. This compensatory mechanism aids in restoring epidermal barrier function and reducing inflammation. Furthermore, 1α,25(OH)₂D₃ controls its own levels in keratinocytes by stimulating CYP24A, an enzyme capable of degrading 1α,25(OH)₂D₃ and preventing overabundance. This feedback system ensures that a very small amount of 1α,25(OH)₂D₃ can leave the skin and enter the bloodstream. Moreover, when keratinocytes differentiate, CYP27B1 activity changes. Accordingly, the highest activity is recorded in undifferentiated cells and the stratum basale of the epidermis. TNF-α and IFN-γ are two pro-inflammatory factors that increase CYP27B1 expression, by mainly enhancing the generation of 1α,25(OH)₂D₃ in response to UV radiation and the disruption of the epidermal barrier [129].

As mentioned previously, via a hydroxylation in the 1α (A ring) position, vitamin D₃ is first transformed into 25(OH)D₃ in the liver, and then is enzymatically converted to 1α,25(OH)₂D₃ in the kidney. 1α,25(OH)₂D₃ binds to the VDRs located both on the cell surface (membrane bound) and inside the immune cell’s cytoplasm (intracellular), and thus, activates both innate and adaptive immune cells [30,137,138,139].

Concerning the innate immune cells and specifically dendritic cells (DCs), 1α,25(OH)₂D₃ is responsible for downregulating the major histocompatibility complex (MHC) class II’s expression, and as a result, antigen recognition and DCs’ activation are induced. When DCs are activated, the vast activity of T-lymphocytes (T cells) is triggered and vice versa, while 1α,25(OH)₂D₃ suppresses pro-inflammatory cytokines’ (i.e., IL–2) production and encourages anti-inflammatory cytokine generation [30]. Regarding macrophages/monocytes, contrastingly, the 1α,25(OH)₂D₃-VDR complex stimulates such leukocytes to produce antibiotic peptides including β-defensin 2 and cathelicidins and enhances via epigenetic programming their immunological memory and differentiation. Furthermore, as of its role in adaptive immunity, 1α,25(OH)₂D₃ participates in the reduction in T-helper cells’ differentiation into T-helper 1 and T-helper 17 (Th1 and Th17, respectively), the upregulation of Th2 cells’ differentiation, the suppression of pro-inflammatory cytokine production, and the enhancement of anti-inflammatory cytokines’ (i.e., IL-10) generation [30]. T cell-derived pro-inflammatory cytokines are finally responsible for inducing B-lymphocytes’ (B cells) differentiation. T cells’ suppression leads subsequently to an indirect downregulation of B cells’ maturation and hence, activity, while direct B cell differentiation and maturation into memory and plasma cells is also encouraged (Figure 6) [30,36,138,139].

4.3. Factors That Affect the Synthesis of Vitamin D

Many factors affect the process by which the skin makes vitamin D when exposed to UV light, known as cutaneous vitamin D synthesis. Maintaining appropriate levels of vitamin D is critical for immune system performance, bone health, and general wellbeing. This mechanism makes this possible. The amount of UV radiation, skin type, location, season, time of day, and use of sun protection are some of the major variables that affect how well vitamin D is produced in the skin. The main factor influencing the synthesis of vitamin D in the skin is the UV light intensity. As mentioned previously, 7-DHC in the skin is changed by UV_B radiation to pre-vitamin D₃, which is then transformed into vitamin D₃. UV_B’s radiation intensity, in general, varies with height, latitude, and cloud cover, among other factors. For instance, UV_B radiation is stronger near the equator and at high altitudes. On the other hand, UV_B intensity drops in the winter and in areas distant from the equator, where vitamin D synthesis is reduced [140].

The effectiveness of vitamin D production is significantly influenced by skin type as well. The pigment melanin, which gives skin its color, absorbs UV rays and lessens their ability to penetrate the skin’s deeper layers. As a result, those with darker skin display higher melanin levels, and are less able to synthesize vitamin D than people with lighter skin. Skin types are categorized on the Fitzpatrick scale from I (very light) to VI (extremely dark), with darker skin types needing more sun exposure to generate the same amount of vitamin D in contrast to lighter skin types [141]. In addition, geographical differences in solar UV_B exposure have a significant impact on vitamin D production. More direct sunshine is received year-round in areas near the equator, which promotes steady vitamin D synthesis. Higher-latitude regions, on the other hand, undergo notable seasonal fluctuations. For instance, there may be insufficient UV_B sunlight during the winter in northern latitudes like Scandinavia or Canada, which increases the risk of vitamin D deficiency. UV_B exposure is also notably influenced by day and season. During the summer, when the sun is at its maximum point, UV_B radiation is more intense. The angle of sunlight decreases the amount of UV_B rays that reach the skin in the winter or in the early morning and late afternoon. For efficient vitamin D synthesis, one must understand the idea of the “solar noon”, or the time when UV_B rays are at their strongest. Hence, exposure to the sun at midday, when UV_B radiation is at its highest, is ultimately more effective in producing vitamin D in individuals [142].

5. Vitamin D Health-Promoting Activities

5.1. Anti-Melanoma and Anti-Cancer Activities

Melanoma is a cancerous condition during which melanocytes—the neutral crest-originated cells responsible for producing melanin (the pigment that gives skin its color)—undergo a transformation, becoming malignant [31,37]. Ultraviolet radiation (UV_R), chemical and biological mediators, including hormonal and non-hormonal regulators, and genetic and molecular modulators are examples of some factors that can regulate the melanogenic activity and action of melanocytes [37,143]. The World Health Organization (WHO) classifies melanoma based on etiology, and more specifically whether it is connected to sun exposure or not, with the former stratified into low- and high-cumulative solar damage (CSD) of the skin. Examples non-related to sun exposure etiology are mucosal, acral, uveal, and Spitzoid melanomas; melanomas developing in blue or congenital nevi; and uncommon melanomas in the central nervous system (CNS) [144,145].

Melanoma is a lethal type of cancer, with a poor prognosis especially when the disease is spread to other body areas. One of the most common types of melanomas is cutaneous melanoma, which has a constantly increasing annual incident rate. Such a type mainly appears in older people, but it has been found in younger people as well. There are a few current treatment schemes, which are unfortunately expensive, and are followed by multiple side effects. Thus, the need for new treatment methods is vastly increasing [32].

It is important to understand how vitamin D may regulate a variety of biological pathways. In more detail, responsible for both the genomic and non-genomic regulation of several biological processes is the binding of 1α,25(OH)₂D₃ to the VDR in the target tissues. As widely accepted, the VDR belongs to the nuclear type of receptor family, which contains ligand-activated transcription factors, and nearly all tissues and cells, including skin cells, are able to express it. According to Podgorska et al. [146], their research indicated that there is an inverse relationship between melanoma progression and VDR expression, proposing that VDR may function as a gene that suppresses melanoma tumors [146]. It is generally acknowledged that vitamin D compounds hold great promise for both the prevention and treatment of cancer, due to their antiproliferative properties towards specific cancer types, predominantly by promoting differentiation and suppressing proliferation [147]. This observation has been confirmed by results deriving from clinical trials on different melanoma types and by epidemiological and preclinical evidence [32,148]. Moreover, both molecular and clinicopathological studies have pointed out a connection between vitamin D signaling abnormalities and the development and the possible outcome of melanoma. As a consequence, successful treatment for melanoma may involve sufficient vitamin D signaling and vitamin D-based interventions [32].

According to Shariev et al. [147], in the human melanoma cell lines used in the investigation, 1α,25(OH)₂D₃ dramatically decreased cell viability and raised caspase levels. Usually during melanoma, the phosphatase and tensin homologue (PTEN), which is a tumor suppressor, is mutated. In this study, results showed an increase in the PTEN levels and a reported downregulation of both the protein kinase B (AKT) pathway and its downstream effectors. Thus, 1α,25(OH)₂D₃ is a potent factor able to efficiently target PTEN and to reduce melanoma cell viability [147].

5.2. Anti-UV Activity

UV_R is a major physical agent that causes skin damage and carcinogenesis through wavelength-dependent processes, such as the chromophore-based absorption of UV_B radiation, reactive oxygen species (ROS), and UV_A reactive nitrogen species production (RNS) [149,150]. Normally, ROS are synthesized in cells endogenously, in a decreased amount, as part of the normal signaling process [25]. UV_B can damage DNA directly via forming cytotoxic cyclobutane-pyrimidine dimers (CPDs), 6-4 pyrimidine photoproducts (6-4PPs), and 8-hydroxy-2′-deoxyguanosine (8-OH-DG), along with the contribution of the generated ROS [25,151]. Additionally, 8-OH-DG, mutations occurring at non-pyrimidine sites, and the so-called “dark CPD” (dCPD) are created by UV_A exposure. Half of the total produced CPDs are formulated by dCPD, which often develop well after UV_A exposure and are dependent on melanin [25]. Crucial in the development of cutaneous carcinogenesis are CPDs and 6-4PP, as they involve the alteration of the p53 gene, a key tumor suppressor [152]. Important defense mechanisms against mutations and photo-carcinogenesis include predominantly the nucleotide excision repair (NER) system, the nuclear factor E2-related factor 2 (Nrf2) with its associated downstream antioxidant components, and the p53 signaling cascade [153].

Vitamin D₃ and its active forms have well-documented photoprotective properties [154,155]. Furthermore, the oral administration of high dosages of vitamin D₃ can cure UV_B-induced skin damage by reducing inflammation and promoting barrier repair mechanisms [156]. Slominski et al. [150] reported that vitamin D₃ prohormone 1α,25(OH)₂D₃ and low-calcemic chemically produced derivatives of vitamin D₃ and 1α,25(OH)₂L₃ offer great protection against UV_R skin damage and cutaneous carcinogenesis [150]. The anti-cancer, anti-melanoma, and anti-UV effects of vitamin D in indicative clinical trials are analyzed in detail in Table 1.

5.3. Wound-Healing Activity

Wound healing is a compilated biological process in which the injured skin is trying to be repaired [157]. Until now, there have been a variety of reagents used in the treatment of such skin wounds. Notably, the greatest of all has been proven to be vitamin D [89]. It is important to mention that increased immunological problems and increased susceptibility to infections are linked to vitamin D deficiency [158].

Epithelial-to-mesenchymal transition (EMT) plays a crucial role in the process of wound healing. Re-epithelialization is one of the vital steps involved in wound-healing processes, in which the migration and proliferation of epidermal keratinocytes take place and surround the lesion [159]. Studies have shown that EMT takes place in keratinocytes at the site of wounds, during re-epithelization [160]. EMT’s onset may be due to tumor growth factor β (TGF-β), a cytokine highly implicated in wound healing [161].

Many processes related to wound healing, such as inflammatory and immune reactions, as well as the proliferation and differentiation of keratinocytes and fibroblasts, may be influenced by vitamin D [162,163,164]. Furthermore, calcium signaling is essential for normal wound healing, where vitamin D has a significant impact on calcium metabolism and vice versa [165]. To demonstrate this delay in wound healing, Oda et al. employed a mouse model missing both the calcium-sensing receptor (CaSR) and the VDR [166]. Studies have also shown that calcipotriol is able to reduce redness, thickening, or other types of discomforts caused by different skin diseases [167]. According to Wang et al., calcipotriol has been shown to have positive effects on the process of wound healing both in vivo and in vitro, as it can promote skin keratinocyte migration and wound healing via suppressing the Hippo signaling pathway [157].

5.4. Antioxidant Activity

Vitamin D was first recognized as an antioxidant in 1993, and since then, research has clarified its antioxidant function mechanisms [35]. Interestingly, vitamin D enhances the expression of antioxidant genes and inhibits oxidative stress pathways, while reducing the accumulation of harmful molecules like advanced glycation end-products. Vitamin D, like other antioxidants, plays a crucial role in neutralizing ROS and RNS, which are major mediators of oxidative stress [168]. This oxidative damage contributes to skin aging, inflammation, and various skin diseases’ onset. Antioxidants aid in maintaining skin integrity by reducing ROS and RNS levels, thus protecting cellular structures like lipids, proteins, and DNA from oxidative damage [35].

The vitamin D hormone contributes to neutralizing oxidative stress by activating the Nrf2 pathway, a critical/master regulator of the antioxidant response [168]. This activation subsequently enhances the expression of antioxidant enzymes, which protect against oxidative damage in skin cells [34]. Nrf2 also induces the action of cytoprotective genes essential for redox balance and detoxification, which partake in protecting against various diseases and aging. Moreover, vitamin D increases total antioxidant capacity by raising superoxide levels [169]. Additionally, vitamin D plays a protective role in mitochondria by regulating ROS production and preventing lipid peroxidation, a crucial activity for the insurance of cellular integrity. A deficiency in vitamin D can lead to increased ROS and oxidative damage, especially in mitochondria. By activating the Nrf2 pathway, vitamin D helps mitigate mitochondrial damage, reduces oxidative stress, and favorably supports the regulation of several inflammatory responses [169].

Human skin naturally produces vitamin D upon exposure to UV rays. This hormone serves as a regulator in maintaining skin homeostasis by influencing various cellular processes, like proliferation, differentiation, and apoptosis processes of skin cells. As an antioxidant, vitamin D can mitigate the damage caused by excessive UV exposure, which leads to ROS formation. By reducing this UV-induced oxidative stress, vitamin D aids in preventing skin damage, inflammation, and even skin cancer development [170].

Furthermore, vitamin D enhances the expression of antioxidant enzymes, such as GSH, which generally neutralizes ROS. Furthermore, it boosts the skin’s immune responses and enhances the activity of enzymes such as superoxide dismutase (SOD) that disarms superoxide radicals, with great efficacy. Such a protective intervention is crucial in maintaining the skin’s barrier function and preventing conditions like eczema, psoriasis, and acne [170]. Vitamin D’s antioxidant properties extend to repairing oxidative damage by modulating DNA repair mechanisms [171]. It also ensures the removal or repair of damaged DNA segments caused by ROS, further preventing mutations and carcinogenesis’ onset in skin cells [170,171]. Studies have highlighted the broader antioxidant framework that includes other vitamins like E and C, flavonoids, and polyphenols, which work synergistically and collaboratively to protect ones’ skin from oxidative stress, and thus the overall skin health [170].

5.5. Anti-Inflammatory Activity

Vitamin D’s anti-inflammatory qualities are essential for healthy skin maintenance, as it keeps inflammation under control by regulating both innate and adaptive immune responses and subsequently ensures the skin’s safety against illness, while efficiently fostering healing and barrier function. Because of this, vitamin D plays a crucial role in the treatment and prevention of inflammation-related skin disorders [27,172]. Vitamin D exhibits anti-inflammatory properties through its active metabolite 1α,25(OH)₂D₃, which binds to the VDR present in various skin cells such as keratinocytes, fibroblasts, and immune cells like macrophages and dendritic cells [30]. This interaction not only regulates calcium homeostasis, but also modulates immune responses, by primarily reducing inflammation and promoting skin barrier integrity [27,172].

Reducing pro-inflammatory cytokines is one of vitamin D’s most significant impacts observed in several inflammation-related disorders [30,173]. Regarding skin inflammation, 1α,25(OH)₂D₃ suppresses cytokines implicated in initiating inflammatory reactions, such as interleukins 2 and 17 (IL-2 and IL-17), as well as TNF-α. Reduced inflammation is linked to this suppression, which alters the immune response from a pro-inflammatory Th1/Th17 state to a more tolerogenic Th2 state [172]. This alteration is notably helpful in the treatment of inflammatory skin conditions including acne, eczema, and psoriasis, because these cytokines are major pathogens in these conditions [128,129,130]. Additionally, vitamin D stimulates the production of regulatory T cells (T-regs), essential for promoting the immunological tolerance maintenance and avoidance of exaggerated inflammatory responses [172]. T-regs also aid in reducing skin inflammation by producing anti-inflammatory cytokines like IL-10. Vitamin D contributes to maintain a more regulated immunological milieu by increasing T-reg activity, which actively induces in turn the prevention of chronic inflammation that could possibly cause skin damage [172].

To further reduce inflammation, vitamin D also aids in the regulation of innate immune responses in the skin [172]. Vitamin D, in fact, reinforces the skin’s defense mechanisms against infections, by directly stimulating antimicrobial peptides such as cathelicidin and β-defensins, while also lowering inflammatory reactions [172,174]. Such dual function emphasizes how crucial vitamin D is for preserving skin homeostasis [27,172]. Beyond its direct immune-modulatory effects, vitamin D also plays a role in inhibiting oxidative stress, which is often a trigger for inflammation. By reducing the levels of ROS in the skin, vitamin D minimizes oxidative damage that can lead to chronic inflammatory states. This antioxidant action works in synergy with immune-modulatory functions, to protect the skin from both internal and external inflammatory stimuli [27].

5.6. Anti-Aging Activity

An intricate process of both internal and external variables contributes effortlessly to skin aging. Like all other organs, the physiological, morphological, and functional characteristics of the skin gradually deteriorate with age. In general, aging is a multifactorial process, as a natural and genetically predisposed phenomenon [27]. More specifically, genetically predetermined intrinsic aging, commonly called chronological aging, is driven by genetic factors and the passage of time and starts around the mid-20s [28]. It entails a slower synthesis of collagen and elastin, two proteins necessary to preserve skin firmness and suppleness, as well as a progressive reduction in the skin’s capacity to regenerate. As a result, the skin thins, loses volume and elasticity, and develops fine lines and wrinkles, whereas dryness and a lifeless complexion result from cellular turnover deceleration, where the skin becomes more brittle and less able to preserve moisture [27].

Conversely, extrinsic aging results from environmental factors such as pollution, UV radiation, and also lifestyle choices like smoking and bad dietary habits [175]. The main cause of photoaging is UV radiation, and particularly UV_A rays that induce collagen fibers to break down and aberrant elastin to be produced, which results in deeper wrinkle formation, a leathery texture, and pigmentation changes like age spots or hyperpigmentation [27]. Additionally, UV radiation produces ROS that expedite further extracellular matrix (ECM) damage, which accelerates the aging process of the skin by degrading collagen and elevating the expression of enzymes like matrix metalloproteinases (MMPs). Additionally, air pollution, smoking, and oxidative stress are in accordance with the breakdown of collagen and elastin, worsening skin texture and elasticity. Smoking reportedly reduces blood flow of the skin, depriving it of oxygen and nutrients, while pollution introduces free radicals that damage skin cells [28,175]. Chronic stress, poor diet, and sleep deprivation can all hasten these consequences by interfering with skin regeneration processes [27]. As a sequel, the skin becomes drier and thinner due to collagen loss [28,175,176].

The impairment of the skin’s collagen partakes in a condition called dermatoporosis [177]. Normally, young skin contains more than 75% of collagen [178,179]. As collagen is the protein of the skin responsible for strength and elasticity, aging leads to thinning and fragility. Studies have shown that vitamin D can act as a stimulating agent for the synthesis of collagen that promotes skin’s thickening and resilience [177]. Also, vitamin D influences the collagen turnover, by repairing and replacing collagen, reducing collagenase, and stimulating collagen production. Collagenase is particularly an enzyme that breaks down collagen [27]. Thus, vitamin D acts equally both as an antioxidant and an anti-aging agent, with great efficacy and promising outcomes [25].

Vitamin D participates dexterously in slowing the aging process, acting as a powerful “anti-aging shield” at both a cellular and a molecular level. Its anti-aging effects are attributed to its regulatory functions in immune modulation, inflammation control, and the maintenance of skin homeostasis. 1α,25(OH)₂D₃ impacts a wide range of biological processes, indisputably crucial for healthy aging [27,34].

Cellular senescence is another hallmark of aging, characterized by the cessation of cell division and the secretion of inflammatory mediators, known as the senescence-associated secretory phenotype (SASP). As people age, senescent cells proliferate and contribute to tissue malfunction and persistent inflammation [34]. It has been demonstrated that vitamin D prevents the accumulation of senescent cells and modulates pathways involved in cell cycle regulation, in order to counteract cellular senescence [34,180]. Vitamin D reduces the expression of senescence markers and inflammatory mediators in aging cells, aiding in maintaining cellular function and tissue integrity. This protective effect extends to various tissues including the skin, where vitamin D prevents at a great extent the breakdown of collagen and elastin [34].

One of the main contributors to aging is mitochondrial malfunction. The energy-producing organelles in cells, namely mitochondria, lose productibility with age, which increases the production of ROS and decreases energy output. This leads to weariness, cellular damage, and a general deterioration in tissue function. Vitamin D improves mitochondrial function and lowers oxidative stress, which subsequently enhances mitochondrial protection [34]. Moreover, it promotes mitochondrial biogenesis, a process that creates new mitochondria organelles and keeps cells healthy and able to produce energy as we age [34]. The anti-inflammatory, antioxidant, and anti-aging effects of vitamin D in several indicative clinical trials and studies are presented in detail in

Table 2. The wound-healing, anti-inflammatory, antioxidant, and anti-aging activities of Vitamin D.

Study Hypothesis	Cosmetic Application	Main Activity	Experimental Pathway—Review Target	Results	Ref.
Vitamin D and calcium are critical for the activation, migration, and function of stem cells during wound healing	In vivo	Wound Healing	Mouse models with full-thickness skin biopsies (control and receptor-deficient) were utilized to assess healing, regarding the fact that vitamin D and calcium aid wound healing by activating VDR and CaSR receptor pathways	Deletion of VDR and CaSR: Delayed wound healing Impairing re-epithelialization Reducing stem cell activity Findings suggested that vitamin D deficiency may cause chronic or delayed healing	[162]
Vitamin D modulates inflammation, supports keratinocyte function, and promotes tissue regeneration to improve wound healing	In vivo	Anti-inflammatory Role in Wound Healing	The key pathway, Vitamin D–VDR signaling, regulates The Wnt/β-catenin cascade for keratinocyte function and skin regeneration Inflammation control, by reducing pro-inflammatory cytokines’ generation Re-epithelialization, aiding keratinocyte migration and skin barrier repair, which was also this review’s predominant confirmation target	Vitamin D aids in successful wound healing, by reducing inflammation, promoting keratinocyte growth and migration, and accelerating re-epithelialization	[181]
Vitamin D protects against aging by modulating immunity, reducing inflammation, and enhancing overall health	In vivo and in vitro	Anti-inflammatory and Anti-aging Effects	Vitamin D–VDR signaling regulates immunity and reduces inflammation, while inhibiting NF-kB, and lowers inflammatory cytokine production	Vitamin D contributes to Reducing effectively chronic inflammation Suppressing pro-inflammatory cytokines (e.g., TNF-α, IL-6) Promoting Tregs and inhibiting pro-inflammatory Th1 and Th17, for immune tolerance Delaying cellular aging by supporting mitochondrial function and DNA repair, while reducing oxidative stress	[34]
Vitamin D’s role as an antioxidant that modulates ROS in keratinocytes, while potentially influencing skin health/disease prevention by reducing oxidative stress	In vivo	Anti-inflammatory and Antioxidant	Keratinocytes were used to examine vitamin D’s cellular impact—effects The reduction in ROS was measured by the activity of antioxidant enzymes like glutathione peroxidase (GPx), which neutralizes harmful peroxides such as hydrogen peroxide (H2O2)	Vitamin D reduces the levels of ROS in keratinocytes, so as to protect cells from oxidative stress and to promote healthier skin, by mainly alleviating inflammation and damage caused by oxidative agents	[170]
Vitamin D (especially its D3 metabolite) induces beneficial anti-aging and photoprotective effects on the skin	In vivo	Anti-aging, Photoprotective (Anti-UV), Anti-inflammatory, Antioxidant	The pathways involved are the VDR and Nrf2 The Nrf2 pathway specifically is crucial for combating oxidative stress and providing photoprotection, while p53 activation supports further DNA repair	Vitamin D induces the activation of pathways that reduce ROS, inhibit DNA damage, and promote DNA repair, protecting the skin from premature aging and photoaging, mostly due to its antioxidant and anti-inflammatory profile	[27]
Vitamin D can act as a protective agent against aging by regulating cellular processes such as oxidative stress, immune response, and mitochondrial function	In vivo and in vitro	Anti-aging, Photoprotective (Anti-UV), Anti-inflammatory, Antioxidant	The Nrf2-Keap1 pathway, activated by Vitamin D, combats oxidative stress The NF-kB pathway, on the contrary, mainly reduces enhanced inflammation Both pathways are essential for vitamin D’s anti-aging and other protective effects	Vitamin D has several anti-aging-associated properties: It acts as an antioxidant via the Nrf2-Keap1 pathway It reduces inflammation through the NF-kB pathway It protects against mitochondrial dysfunction and ROS accumulation Its metabolites support DNA repair, helping to reduce UV-induced skin damage	[34]

.

6. Skin Conditions and Evidence of the Beneficial Role of Vitamin D

Vitamin D’s immunomodulatory actions are generally mediated via its binding to the VDR, present in keratinocytes and immune cells. Such interaction influences gene expression, resulting in a reduced generation of pro-inflammatory cytokines (e.g., IL-6, IL-17, and TNF-α), increased T-reg action and production of anti-inflammatory IL-10, and enhanced antimicrobial peptide expression, thus boosting immunity [139,182,183]. Newly emerged technological vitamin D applications, photodynamic therapy (PDT) exploitation, melanoma or non-melanoma skin cancer prevention, and vitamin D combination treatments with corticosteroids or calcineurin inhibitors have shown superior outcomes in reducing inflammatory skin disease symptoms [31,64,184,185]. Concerning several disorders, including psoriasis, atopic dermatitis, vitiligo, acne vulgaris, and acne rosacea, vitamin D has been successfully implicated and integrated in many cosmetic, cosmeceutical, and nutraceutical/nutricosmetic applications, and some clinical trials and vitamin D-based applications will be further discussed in the following sections. All mentioned dermatological disorders connected with vitamin D levels, are presented in Table 3.

6.1. Psoriasis

Psoriasis is characterized as a chronic, inflammation-related skin disease that affects approximately 2–3% of the worldwide population, causing significant morbidity [186]. The pathogenesis of this disease is not fully understood yet, but research has shown that it is linked to the impairment of immune cells in the skin. More specifically, T cells are the ones possessing a crucial role in the development of psoriasis [89,187].

Psoriatic fibroblasts were demonstrated to be somewhat resistant to the antiproliferative actions of 1α,25(OH)₂D₃ in 1985 [188]. This observation triggered the outbreak of theories suggesting that oral vitamin D, and subsequently its topical preparations, would be useful in treating hyperproliferative skin conditions. While the introduction of topical vitamin D analogs notably altered the treatment of psoriasis, the oral use of vitamin D₃ as a therapeutic failed due to the risk of hypercalcemia [37]. Vitamin D analogs such as calcipotriol are widely used to manage psoriasis plaques, as they regulate keratinocyte proliferation and differentiation. Vitamin D suppresses Th1- and Th17-mediated inflammation and reduces pro-inflammatory cytokines like IL-17 and TNF-α [36,189,190,191].

Numerous investigations have revealed extremely decreased serum vitamin D levels in psoriasis patients; however, the significance of this discovery is still quite blurry. It is recommended that patients with low serum vitamin D levels should be provided with oral vitamin D₃ supplements, so as to avoid bone mineral density loss and comorbidities associated with psoriasis [192], given that a diet high in vitamin D is believed to place a positive impact on various comorbidities (i.e., obesity, diabetes mellitus, metabolic syndrome, cardiovascular events) [193]. The cornerstone of treatment for mild to severe psoriasis is topical vitamin D analogs, either alone or in conjunction with topical corticosteroids, especially betamethasone [81]. Especially the use of topical calcipotriol has been proven as a safe treatment in cases of localized plaque psoriasis (Table 3) [37,194].

Table 3. Dermatological Disorders connected with Vitamin D levels.

Disease	Type of Vitamin D’s Association	References
Psoriasis	Chronic inflammation and immune system dysregulation (specifically T cells), linked to vitamin D deficiency and associated with various comorbidities (e.g., obesity, diabetes, cardiovascular events), which responded to vitamin D analogs (topical treatment), effectively	[37,89,186,187,188]
Atopic dermatitis (AD)	Increased prevalence at higher latitudes, due to reduced sun exposure and decreased vitamin D production Characterized by epidermal barrier dysfunction and immune system dysregulation, and linked to low serum vitamin D levels (especially in moderate to severe AD and lighter skin types) Topical vitamin D analogs are contraindicated, as they can exacerbate the condition by inducing TSLP-related inflammatory responses	[38,39,40,41,195,196,197,198,199]
Vitiligo	Autoimmune pigmentary disorder, initiated by melanocyte destruction, leading to depigmented patches Vitamin D plays a crucial role in restoring melanocyte function, through modulating T cell activation, but its effectiveness (both oral and topical) in treatment remains inconsistent The combination of topical vitamin D analogs with corticosteroids or calcineurin inhibitors enhances repigmentation; however, a combined use with phototherapy is not recommended	[42,43,89,200]
Acne vulgaris	Common inflammatory skin disorder, related to immune response targeting Propionibacterium acnes Vitamin D suppresses Th17 differentiation induced by P. acnes, being a potent candidate for controlling acne Sebocytes respond to 1α,25OH2D3, indicating that vitamin D analogs may be beneficial in acne management	[44,89]
Acne rosacea	A chronic skin disorder, primarily affecting the face, that is associated with elevated serum vitamin D levels, potentially indicating a link between increased vitamin D and the subsequent decrease in the risk development of rosacea	[201]

Table 3. Dermatological Disorders connected with Vitamin D levels.

Disease	Type of Vitamin D’s Association	References
Psoriasis	Chronic inflammation and immune system dysregulation (specifically T cells), linked to vitamin D deficiency and associated with various comorbidities (e.g., obesity, diabetes, cardiovascular events), which responded to vitamin D analogs (topical treatment), effectively	[37,89,186,187,188]
Atopic dermatitis (AD)	Increased prevalence at higher latitudes, due to reduced sun exposure and decreased vitamin D production Characterized by epidermal barrier dysfunction and immune system dysregulation, and linked to low serum vitamin D levels (especially in moderate to severe AD and lighter skin types) Topical vitamin D analogs are contraindicated, as they can exacerbate the condition by inducing TSLP-related inflammatory responses	[38,39,40,41,195,196,197,198,199]
Vitiligo	Autoimmune pigmentary disorder, initiated by melanocyte destruction, leading to depigmented patches Vitamin D plays a crucial role in restoring melanocyte function, through modulating T cell activation, but its effectiveness (both oral and topical) in treatment remains inconsistent The combination of topical vitamin D analogs with corticosteroids or calcineurin inhibitors enhances repigmentation; however, a combined use with phototherapy is not recommended	[42,43,89,200]
Acne vulgaris	Common inflammatory skin disorder, related to immune response targeting Propionibacterium acnes Vitamin D suppresses Th17 differentiation induced by P. acnes, being a potent candidate for controlling acne Sebocytes respond to 1α,25OH2D3, indicating that vitamin D analogs may be beneficial in acne management	[44,89]
Acne rosacea	A chronic skin disorder, primarily affecting the face, that is associated with elevated serum vitamin D levels, potentially indicating a link between increased vitamin D and the subsequent decrease in the risk development of rosacea	[201]

6.2. Atopic Dermatitis

Greater geographic latitudes display greater rates of atopic dermatitis (AD), which is correlated with reduced sun exposure and a decreased generation of vitamin D [195]. AD is a chronic, recurrent inflammatory disease, characterized by pruritus and eczematous lesions, that affects approximately 20% of children and 7.2% of adults, globally [41]. The primary cause of AD is the malfunction in the synthesis of the epidermal barrier and a change in the cutaneous immune system, which impacts mainly filaggrin [196]. Topical vitamin D enhances skin barrier function by promoting keratinocyte differentiation and the formation of antimicrobial peptides like cathelicidin, therefore decreasing Staphylococcus aureus colonization, which is a common aggravating AD factor [202,203].

Vitamin D is known to regulate the integrity and permeability of the epidermal barrier, although its exact role in this process is still unknown [38]. There has been a long debate concerning the efficacy of oral vitamin D as an AD supplement. Low serum vitamin D levels, especially during winter, have been linked in several studies to the progression and severity of the illness. However, the exact role that vitamin D plays in the pathophysiology of AD remains unclear [197]. Serum vitamin D levels were shown to be considerably lower in moderate and severe AD than in mild AD, in a recent study conducted in Spain, but this link was only significant for patients with light Fitzpatrick skin types (study involving 134 children with AD and 105 control samples, without AD) [40].

To sum up, there is no clear evidence pointing out the importance of dietary vitamin D as an AD treatment [39]. Further investigation should be conducted to prove the importance of vitamin D supplementation in such types of patients. Conversely, animal investigations using topical vitamin D analogs have been claimed to cause AD, mostly via activating TSLP in keratinocytes [198]. TSLP acts as a switch for the T-helper 2 (Th2) allergic inflammation, a common characteristic of AD, and is necessary for the induction of pro-inflammatory chemokines—mostly IL-4, IL-13, and IL-31 in AD (Table 3) [199].

6.3. Vitiligo

Vitiligo is a pigmentary disorder, initially induced by the breakdown of functioning melanocytes in the epidermis, which formulate, as a result, well-defined, depigmented patches or macules of varying sizes and forms [89]. Vitamin D acts as protection in the epidermal melanin unit and contributes to restoring melanocyte integrity, through many ways like the activation, proliferation, and migration of melanocytes, and pigmentation cascades. Such properties derive from their ability to modulate T cell activation, which is probably correlated with melanocyte disappearance in vitiligo [89].

Vitiligo is an autoimmune skin disorder, and due to various vitamin D favorable effects, oral vitamin D supplements could be used in vitiligo therapy. However, multiple studies with incompatible results regarding the efficacy of oral vitamin D in treating vitiligo must not be overlooked [89,200]. A confliction also exists about topical vitamin D analogs’ ineffectiveness [200]. Useful in enhancing clinical repigmentation is combining topical vitamin D analogs with topical corticosteroids or the topical calcineurin inhibitor [43]. Furthermore, it is not advised to combine vitamin D analogs with phototherapy [42]. Narrowband UV_B phototherapy combined with topical vitamin D has shown increased efficacy in repigmentation, as compared to phototherapy alone, by triggering melanogenesis and regulating immune responses in vitiligo cases (Table 3) [54,204,205].

6.4. Acne Vulgaris and Acne Rosacea

Acne vulgaris is one of the most common skin disorders affecting many people worldwide. Acne vulgaris’ pathogenesis relates to inflammation, mainly enhanced by immune response and specifically targets Propionibacterium acnes [89]. Recent study outcomes have shown that P. acnes is a strong Th17 inducer and that 1α,25(OH)₂D₃ suppresses Th17 differentiation generated by P. acne, which may be useful in controlling acne [44]. Plus, it was demonstrated that sebocytes are 1α,25(OH)₂D₃-responsive target cells, suggesting that vitamin D analogs might be useful in acne management, as vitamin D deficiency is pronounced in acne vulgaris patients [44,46]. Vitamin D has pleiotropic effects in preventing acne vulgaris lesions, through directly inhibiting cell division, decreasing sebum secretion and pore blockage, and impeding Cutibacterium acnes’ growth [206].

Similarly, another study suggested that in patients with rosacea, a high level of serum vitamin D was traced. Rosacea is a chronic skin disorder that mainly affects an individual’s face and is generally recognized by symptoms including flushing or long-term redness, especially in the nose and cheeks. Study findings have suggested that elevated serum 1α,25(OH)₂D₃ may be correlated with a lower risk of incidence and further development of rosacea [201,207]. However, the link between vitamin D levels and rosacea remains inconclusive, necessitating further research to clarify its therapeutic role [47]. Vitamin D’s anti-inflammatory actions may aid in mitigating redness and pustule formation in rosacea, while considering acne vulgaris, vitamin D reduces sebum formation and inhibits Cutibacterium acnes-induced inflammation (Table 3) [201,207,208].

7. Vitamin D in Cosmetics and Cosmeceuticals

Vitamin D has become an important part of dermatology because of its many advantages concerning skin health [209]. Its usefulness in different topical formulations, its underlying mechanisms of action, and its therapeutic efficacy in treating skin disorders have been brought to light by current scientific breakthroughs. Vitamin D is already used in skincare products in a variety of ways, each designed to meet unique dermatological requirements [81,124,210]. This hormone can, for instance, be found in creams, which are made to provide specific troubled skin areas with high concentrations of bioactive substances. When treating illnesses like psoriasis and AD, where localized treatment is vital, cosmetic formulations involving vitamin D have reportedly exhibited great results [121]. Because of their thick texture, creams can be applied deeply into the layers of the afflicted skin. In contrast to creams, lotions are designed with a lower viscosity and are appropriate for daily use. Lotions are therefore perfect for efficiently covering bigger body areas. Because of their thinner texture, vitamin D may be applied consistently, offering broad coverage. Moreover, sprays offer a practical way to get vitamin D into difficult-to-reach areas, providing a non-greasy substitute for creams and lotions, which makes them useful for people looking for a simple and fast application technique [121].

Ointments work well on excessively dry or irritated skin because of their thick, occlusive texture [211]. Such mixtures are dedicated to improving the absorption of vitamin D by creating a barrier, which prolongs the feeling of comfort and hydration. Because of their propensity to stay on the skin for a long time period, vitamin D has plenty of time to enter the body and initiate its function. Lighter options are provided by serums that are frequently mixed with different active components, which in turn, due to their composition, are less residual and enable tailored vitamin D administration [27]. Because of their quick absorption, serums are very helpful for targeted therapy regions. Vitamin D can also be found in infused oils mixed with ones, to increase their moisturizing capabilities, enhance their particularly helpful profile for people with dry skin types, and offer several therapeutic effects that improve the overall skin health. Numerous anti-aging and photoprotective effects towards human skin health, of vitamin D₃ and its active metabolites, derive from their utilization in cosmetic formulations [27]. These positive outcomes are accomplished by immunomodulation, which also regulates keratinocyte proliferation and differentiation so as to provide the epidermal barrier the ability to preserve skin homeostasis. Furthermore, vitamin D products trigger antioxidative reactions, prevent DNA damage, and promote DNA repair to reduce the risk of cancer’s onset and premature skin aging. The activities of lumisterol metabolites are indeed comparable [27].

It is important to mention that the most frequently utilized type of vitamin D in skincare is vitamin D₃. Because of its higher efficacy and stability, vitamin D₃ is preferred in skincare products over vitamin D₂. When it comes to increasing and/or preserving vitamin D levels in the body, vitamin D₃ is notably superior to vitamin D₂, while being more stable, ensuring that the medicine sustains its potency over time. Furthermore, because of its stability and efficacy, vitamin D₃ is the recommended ingredient in a variety of skincare formulations, such as oils, serums, ointments, lotions, and creams, as it keeps its effectiveness in a variety of formulations and blends in well with other active components [121,212]. In addition, calcipotriol and 1α,25(OH)₂D₃, two forms of vitamin D₃, are widely used to treat skin diseases including psoriasis. By slowing down the skin cells’ fast proliferation, calcipotriol, namely a synthetic derivative of vitamin D₃, is topically applied to treat the symptoms of psoriasis. Plus, the active 1α,25(OH)₂D₃ is used as well in a plethora of medical applications, due to its strong potency against skin diseases [121].

Vitamin D is categorized as an active ingredient in medicine. The European Union prohibits the use of vitamin D₃ and D₂ in cosmetic formulations (No. 335 in Annex II of Regulation (EC) No. 1223/2009) [213]. Nevertheless, in the CosIng database, a vitamin D precursor, 7-dehydrocholesterol, is characterized as an emulsion-stabilizing, skin-conditioning, and viscosity-controlling ingredient [214]. Vitamin D provitamins are allowed to be used in cosmetic and cosmeceutical formulations. Notably, the European Cosmetics Directive explicitly bans the use of both ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃). However, this does not apply to provitamins that are licensed in the US, for their utilization in skincare products [25,215]. Several examples of products utilizing vitamin D in the form of provitamins exist, including anti-aging day and night creams, serums, and many other formulations deriving from numerous global companies. Moisturizers enriched with vitamin D improve hydration and reduce transepidermal water loss, benefiting dry and sensitive skin [216]; vitamin D-based anti-aging serums regulate collagen synthesis and reduce oxidative stress [34]; and topical vitamin D formulations may regulate melanogenesis, addressing melasma and uneven skin tone [217,218].

As mentioned before, a whole series of interesting effects in the skin are described in the context of vitamin D. To begin with, calcitriol has an impact on keratinocyte development and differentiation, playing a crucial function in the therapy of psoriasis [219]. In parallel, the skin’s calcium gradients are properly maintained by calcitriol [25]. Stimulation for the formation of anti-microbially effective peptides, like defensins and cathelicidins, is another function activated by 1α,25(OH)₂D₃. The impact of such peptides is interesting in the context of inflammatory processes in neurodermatitis cases [220]. Furthermore, calcitriol prolongs the self-protection of the skin during the UV_B radiation exposure, by stimulating heat shock proteins. Lastly, several studies [221,222,223] describe a repigmentation in vitiligo cases, after the application of calcitriol or vitamin D analogous products. In

Table 4. Possible cosmetic and cosmeceutical formulations containing vitamin D.

Cosmetic Type	Purpose of Vitamin D	Effects	Examples	References
Moisturizers	Enhances hydration and skin barrier function	Improve moisture retention and sooth dry skin	Vitamin D3 creams, hydrating lotions	[216]
Anti-aging products	Supports skin homeostasis, reduces oxidative stress, improves elasticity	Stimulate DNA repair, enhance collagen production, antioxidant and anti-photoaging property, reduce wrinkles	D3 anti-aging serums	[27,28,34,224]
Acne treatments	Reduces inflammation and promotes healing	Reduce skin sebum, clear acne scars	Acne serums with vitamin D	[225]
Psoriasis treatments	Reduces inflammation	Help keratinocyte regeneration	Ointments	[219,226,227,228]
Cleansers	Mild exfoliation and hydration	Cleanse without stripping natural oils	Cleansers with vitamin D derivatives	[121]
Scalp treatments	Improves scalp health and prevents dandruff	Reduce flakiness, support hair follicle health	Shampoos, hair oils, and scalp serums	[210]
Hand creams	Repairs cracked skin, enhances hydration	Improve moisture retention and sooth dry skin	Hand creams with vitamin D	[229]

, various cosmetic and cosmeceutical formulations are described.

7.1. Mechanism of Action

The mechanism of action of vitamin D when applied topically to the skin consists of several complex biological processes that contribute to its therapeutic effects [74,81].

Topical vitamin D formulations mostly act locally within the skin in contrast to systemic vitamin D ones, which are converted to their active form in the liver and kidneys. After being applied topically, vitamin D in the form of calcitriol or its analogs interacts with particular skin cellular targets, to produce its advantageous effects. One of the main mechanisms of action involves the VDR, which is expressed in various skin cells including keratinocytes, fibroblasts, and immune cells. The primary mode of action is via its VDR interaction, where the N-terminal DNA-binding domain of the VDR transcription factor binds to vitamin D response elements (VDREs) on DNA, the C-terminal ligand-binding domain, and the hinge region that joins these transcription factors’ three primary domains. After binding to the ligand 1α,25(OH)₂D₃, its 12 helices in the ligand-binding domain undergo conformational changes that ultimately enable the domain to interact with coactivators and its heterodimer partner, which is usually the RXR [74].

VDR attaches itself to VDREs, which are primarily direct repeats of hexanucleotides, spaced three nucleotides apart (DR3 call II gene motifs). This binding enhances the recruitment of several coregulatory complexes necessary for the genomic VDR action. Due to the gene- and cell-specific nature of these complexes, precise control over gene expression is possible. Coactivators with histone acetyltransferase activity, such as the non-receptor, protein-tyrosine kinase (SRC) family, and corepressors with histone deacetylase activity, like the silencing mediator of retinoic acid and the thyroid hormone receptor (SMRT), as well as the nuclear receptor corepressor (NCoR), are examples of coregulators. Methyltransferases, demethylases, adenosine triphosphate (ATP)-ase-containing nucleosomal remodeling complexes, and elements of the mediator complex interacting with RNA polymerase II are other interesting factors linked to the VDR cascade [74].

This multifaceted procedure encourages keratinocytes to differentiate and proliferate, a necessary action for preserving the skin barrier. By upregulating genes involved in keratinocyte differentiation and cornification, vitamin D strengthens the skin’s protective layer and promotes the development of a functioning stratum corneum. Furthermore, topically applying vitamin D promotes the synthesis of antimicrobial peptides such as cathelicidins, which are essential for the skin’s innate immune response, as they support the skin’s defensive processes and aid in the fight against infections. Vitamin D helps the skin keep itself healthy and fight off infections, by improving the synthesis of cathelicidins [37]. Additionally, using vitamin D topically shields the skin from harm caused by UV rays. Antioxidant qualities of vitamin D contribute, in fact, to lessening oxidative stress acceleration by the UV light. The advantages of vitamin D in preserving skin health and averting UV-induced premature aging are consequently more and more clear [37].

The anti-inflammatory properties of vitamin D play a critical role in its skin activity [27,37,230]. By upregulating anti-inflammatory cytokines and downregulating pro-inflammatory ones, vitamin D highly participates in the immune response. This skin-correlated activity is especially helpful in the treatment of inflammatory skin diseases like psoriasis, since it reportedly reduces inflammation and excessive skin cell turnover, mainly by inhibiting T cell proliferation and further regulating the formation and repair of skin cells [37]. Through the facilitation of cellular processes involved in tissue repair and regeneration, it aids in the healing of wounds. Topical vitamin D application also promotes keratinocyte migration and proliferation to the wound site, hastening the closure of wounds and aiding in the repair of injured skin [37]. Vitamin D provides, additionally, defense against UV-induced oxidative stress, due to its antioxidant qualities of effectively neutralizing free radicals, and thus, aids in the prevention of skin damage and premature aging and the promotion of the overall skin resilience and health [37].

Skin health is significantly impacted by vitamin D, and its therapeutic advantages are mediated through several pathways [25]. By maintaining the epidermal barrier and facilitating the development of epidermal keratinocytes, vitamin D encourages the skin to function as a protective barrier, less vulnerable to infection and environmental harm, towards a potential injury and keratinocytes maturing properly [25,27]. Furthermore, this hormone plays a critical role in controlling the proliferation of cells in the epidermis, as it regulates aberrant cell growth, which is important in conditions like psoriasis with increased rates of cell turnover [25]. Finally, vitamin D helps to promote skin health during the skin renewal process, relieves the symptoms of skin-associated comorbidities, normalizes epidermal growth, and enhances cell proliferation as well as repair activities, functions that make this hormone a useful tool in the treatment of wounds and skin injuries, since it primarily speeds up the healing process of injured skin [25].

7.2. Efficacy of Vitamin D

Clinical trials and studies have highlighted the efficacy of vitamin D in managing various skin conditions like psoriasis, wound healing, different types of acne, and UV-induced damage [231,232,233,234]. While these findings are promising, ongoing research is essential so as to fully understand the optimal use and value of vitamin D in skincare. The treatment of psoriasis, a condition marked by thick, scaly patches caused by a rapid turnover of skin cells, is listed among the most investigated uses of vitamin D and its analogs [37,57,231,235,236,237]. One particularly useful synthetic version of vitamin D is calcipotriene. An experiment based on the utilization of calcipotriene exhibited a vast improvement in psoriasis symptoms, especially in lowering plaque thickness and scaling [37]. These results have been validated by other similar research that highlighted the efficacy of topical vitamin D analogs, towards lowering psoriatic plaques without any recorded side effects or adverse observations [238].

The interesting function of vitamin D in wound healing has also been evaluated in several clinical trials [30,94,232,239]. Effective wound healing depends on its role in cell differentiation and proliferation. Vitamin D supplementation has been pointed out both to enhance the wound-healing rates and to shorten the acquired healing time [240]. Recent research outcomes by Q. Chen et al. [239] have demonstrated vitamin D’s crucial role in maintaining skin barrier integrity and reducing the symptoms of chloasma. The findings clearly highlighted that vitamin D, whether applied topically or administrated orally, reduced the chloasma severity and enhanced the wound-healing process [239].

Another topic receiving vast attention has been the use of vitamin D in acne treatment and, for example, in treating acne vulgaris [45,233,241]. Topical vitamin D formulations were observed to reduce inflammation and acne lesions; however, the effects were not as consistent as with other, already widely utilized acne therapeutic interventions [45]. Additionally, vitamin D aids in minimizing UV ray damage and potentially slowing down the skin aging process, while considering photoprotection, vitamin D’s antioxidant qualities could lessen the UV-accelerated oxidative damage [45]. According to research based on how vitamin D affects skin aging, adequate levels of vitamin D in the body may contribute to keeping one’s skin supple and minimizing wrinkles’ appearance, although more studies are required, so as to further validate such benefits [25,45,193].

8. Discussion—Challenges and Controversies

The use of vitamin D in cosmetic products has garnered noteworthy interest owing to its possible advantages for the skin’s wellbeing, such as better wound healing, improved barrier function, and anti-inflammatory properties [242,243,244]. However, issues and disagreements have emerged, regarding the inclusion of vitamin D in cosmetic products, that must be resolved. Stability, bioavailability, efficacy, regulatory difficulties, and possible interactions with other components are only a few of the challenges, where especially vitamin D’s low stability poses a major obstacle for its use in cosmetic products. When exposed to light, heat, and air, vitamin D is prone to deterioration, chiefly in its active forms (D₂ and D₃), while over time this instability may cause the product’s efficacy to decline. Cosmeticians and cosmetic industries, as a result, need to take great caution when creating such formulations, to shield the vitamin D content from any external elements that may degrade it. Stabilizing chemicals and encapsulation techniques are common approaches engaged to improve vitamin D’s stability in cosmetic products. It is difficult to guarantee whether vitamin D cosmetic formulations will benefit our skin, while also owning longer shelf life, and this is the main reason why further investigation upon improving both efficacy and longevity issues is highly necessitated [245].

Another point of contention is the bioavailability of vitamin D when applied topically [54,246,247]. Although the systemic benefits of vitamin D are well established, its efficacy in topical preparations remains uncertain. The composition of the substance and the skin state might affect how well it absorbs and implements vitamin D. Studies have claimed that topical vitamin D may not have a substantial impact on systemic vitamin D levels but may enhance localized effects like lowering inflammation and enhancing skin hydration [216,248]. This limitation raises questions about the overall effectiveness of vitamin D in cosmetics and whether it can provide safe, substantial benefits. Regulatory issues also complicate its cosmeceutical use. Different countries have established varying regulations regarding the use of vitamin D in skincare products, as, for example, while some countries have allowed the inclusion of vitamin D at certain concentrations, others have imposed stricter guidelines [249]. Additionally, concerns about its potential for adverse reactions or interactions with other cosmetic ingredients have recently been raised [250]. The safety profile of vitamin D at high concentrations or when used in combination with other active ingredients, needs to be conclusively and thoroughly assessed [249].

Vitamin D incorporation into cosmetic formulas can be rather expensive, as maintaining its stability, efficacy, and proper function is vital. This may result in higher retail prices, potentially limiting the availability of certain products. Furthermore, market acceptance is also crucial, due to the fact that while many customers recognize vitamin D’s benefits, others may still be skeptical of its effectiveness when applied topically, given its well-established advantages when ingested or produced directly after sun exposure. An additional point of contention is how vitamin D interacts with other active chemicals utilized in cosmetic formulations, such as retinoids, peptides, or antioxidants. While some combinations might increase the product’s overall efficacy, others might cause negative side effects or lessen the final product’s benefits. In order to guarantee that vitamin D stays effective, and that the formulation does not cause unforeseen side effects, understanding these interactions takes substantial research and testing. Consumer education is essential in addressing misconceptions about the role of vitamin D in skincare. There is often confusion regarding the differences between vitamin D’s systemic effects and its topical benefits. Educating consumers about realistic expectations and the specific benefits of topical vitamin D is hence of great importance [245].

The role of vitamin D in skincare is still being investigated from a scientific perspective. So as to completely understand the mechanisms via which topical vitamin D works and to identify the best formulations and doses regarding different skin diseases, further research is required, and current cosmetic formulations may need to be adjusted as new findings emerge. Because scientific research is constantly evolving, it can influence market trends and product development, creating uncertainty for both consumers and manufacturers. Despite the challenges, the use of vitamin D in cosmeceuticals holds significant promise for improving skin health and addressing various dermatological concerns. However, the complexities and controversies surrounding its incorporation must be carefully navigated. Factors including stability, bioavailability, regulatory compliance, cost, and potential interactions with other ingredients are all key elements in shaping vitamin D’s skincare profile. As research progresses and consumer awareness expands, addressing and overcoming these challenges will be crucial for maximizing the benefits of vitamin D, while ensuring both safety and efficacy in cosmeceuticals [245].

9. Future Directions and Research

The application of vitamin D in cosmetics is an area of growing interest due to its potential benefits for skin health. However, to fully realize and harness these benefits, future research and development must focus on several key areas, including optimizing formulation techniques, enhancing bioavailability, comprehending the mechanisms of action, evaluating long-term safety, and exploring innovative delivery systems.

Future research should focus on advancing formulation techniques to improve the stability and efficacy of vitamin D in cosmetics. Vitamin D, particularly in its active forms, is vulnerable to degradation from UV, heat, and air exposure. Innovative encapsulation methods, such as nanoencapsulation or liposomal delivery systems, could provide enhanced protection against environmental factors, thereby extending the shelf life and stability of vitamin D in cosmeceuticals [251]. Moreover, developing new stabilizing agents and excipients that preserve vitamin D’s potency, without also compromising the product’s texture and feel, is crucial, as this will not only improve the quality of vitamin D-based cosmetics, but also ensure their maximum benefits [251]. Additionally, vitamin D could be a key ingredient in orally administered nutricosmetics, designed to improve skin health and appearance. Future research may focus and explore optimal formulations, combining vitamin D with other skin-beneficial nutrients, including collagen, hyaluronic acid, omega-3 fatty acids, polyphenols, biotin, and antioxidants, able to enhance skin hydration, elasticity, and overall vitality [252,253,254,255,256,257,258]. Moreover, the synergistic activity of antioxidants like vitamin C and E with vitamin D [25,254,259], or niacinamide–vitamin D [260] combinations, could offer several cosmeceutical and nutricosmetic benefits against dermatological and skin health conditions.

Sunscreens, a type of cosmetic product, can provide protection to the skin against UV and dermatologists recommend their use [261]. It is unfortune to mention that some of these cosmetic preparations contain chemicals, something that is not safe and can even lead to systemic absorption [262]. To add, not all sunscreens offer protection against UV_A, pollution, infrared light (IR), or blue light and so as to produce vitamin D, UV_B is necessary. More specifically, the role of vitamin D in mitigating oxidative stress could be harnessed in anti-pollution skincare formulations. Plus, as blue light exposure from screens becomes a growing concern, combining vitamin D with other protective agents may aid in counteracting its effects, promoting healthier skin [263]. There are currently no recommended sunscreen usage guidelines or ideal sun protection agents [264]. New active compounds, stable and safe to add to cosmetic compositions [265] that may also function as antioxidant agents preventing photoaging like vitamin D, are therefore needed [266].

One major challenge in the topical application of vitamin D remains as its bioavailability [267]. Enhancing the skin’s capacity to absorb and utilize topical vitamin D should be a primary research goal. By comparing the effectiveness of various vitamin D forms, such as vitamin D₃ and its metabolites, in topical applications, researchers may be able to identify the most suitable variants for topical use. Moreover, its delivery and absorption could also be improved by researching synergistic effects with other compounds, such as penetration enhancers or advanced vehicle systems that enhance skin permeability. Future research on the optimal vitamin D content for various skin types and conditions will help create products tailored to specific dermatological needs [267]. Beyond traditional encapsulation, emerging encapsulation techniques like solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and stimuli-responsive carriers could offer superior protection, and sustained release, and target both oral and topical vitamin D delivery, while improving stability, enhancing bioavailability, minimizing potent degradation, and responding to environmental changes (e.g., pH, temperature, UV exposure) [65,268].

Optimizing vitamin D’s use in cosmetics also requires a deeper understanding of its molecular and cellular actions. Scientists should focus on clarifying the exact pathways through which vitamin D impacts skin health, encompassing its effects on cell differentiation, proliferation, and barrier function. Examining the role of coregulatory proteins and VDR in these processes will provide critical insights into how vitamin D works and how its effects can be maximized in cosmetic formulations. Also, exploring how vitamin D interacts with other signaling pathways, like those connected to oxidative stress and inflammation, may reveal novel therapeutic targets and improve product development. Safety is of paramount importance when formulating cosmetic products, and long-term research is required to evaluate vitamin’s D efficacy. Future studies could explore as well how vitamin D affects melanogenesis and pigmentation pathways. Such product development could lead in successfully targeting pigmentation disorders, like melasma, or developments aiming to even out skin tone (skin tone regulation) [25,269,270].

The skin microbiome plays a vital role in maintaining skin health. Therefore, studies could focus on investigating how vitamin D influences the skin microbiome and whether combining vitamin D with prebiotics, probiotics, or postbiotics in cosmetic, cosmeceutical, and nutricosmetic formulations can lead to enhanced skin barrier function and resilience against environmental stressors [271,272,273]. While vitamin D is essential for overall health, excessive use of high-concentration products over extended periods may have adverse effects. Research should hence focus on long-term safety evaluations, such as potential skin reactions, systemic absorption, and combinations with other topical or systemic treatments. Rigorous clinical trials and post-market surveillance are necessary to guarantee that consumers are not exposed to risks from vitamin D-based cosmetics and that any potential side effects are promptly identified and addressed [269].

Innovative delivery systems offer promising avenues for enhancing the effectiveness of vitamin D in skincare. Research into new delivery methods, such as microneedle systems (e.g., patches), microemulsions, smart skin patches, bioengineered vitamin D precursors, nanoencapsulation carriers, photonic delivery, quantum dot systems, or hydrogel matrices, could enable more efficient and controlled release of vitamin D into the skin. These advanced systems may enhance the penetration and targeting of vitamin D to specific skin layers where it can exert its beneficial effects [72,274,275,276,277,278]. Exploring combination therapies that integrate vitamin D with other active ingredients like antioxidants or anti-inflammatory agents could amplify the overall efficacy of cosmetic products. Although the number of studies describing the emerging technologies appear large at first glance and various strategies have been covered, they are all at an early research stage [64].

As personalized skincare continues to grow in popularity, future studies should investigate vitamin D’s role in customized skincare uses. Individual responses to vitamin D are influenced by genetic and environmental factors; a better understanding of these variables might result in more individualized and efficient treatments. Studying the impact of genetic variations in vitamin D’s metabolism on skin health and sensitivity to topical treatments, as well as how factors like skin type, age, and lifestyle affect vitamin D-based cosmetics, will aid in the development of more tailored and customized products, towards several skin conditions [279]. Additionally, during the rise in machine learning, and artificial intelligence (AI)-driven skincare diagnostics, vitamin D products could be tailored to an individual’s needs. AI tools are able to analyze genetic markers, skin type, and environmental factors, with a view to recommend personalized vitamin D products, ensuring maximum efficacy for different users [280,281]. Three-dimensional bioprinting could revolutionize personalized vitamin D cosmetic formulations, as custom-printed patches or masks, for instance, can deliver precise, individual-specific dosages [282].

Further clinical evidence is essential to support the benefits of vitamin D in cosmetics/cosmeceuticals. Large-scale, carefully monitored clinical trials should assess the effects of vitamin D on various skin disorders, like eczema, acne, and aging [283]. The widely known vitamin D benefits in promoting cell differentiation and proliferation suggest its potential use in wound-healing and scar management applications. Future cosmeceuticals could incorporate vitamin D for post-surgical or post-operative skincare, burn recovery, and minimizing scar appearance, effectively [25,284,285,286,287]. Moreover, as vitamin D plays a significant role in collagen synthesis and photoaging prevention, further studies could elaborate on its interaction with peptides, growth factors, or retinoids to develop comprehensive anti-aging solutions. Such products may target wrinkles, fine lines, and loss of elasticity, improving overall skin health and barrier function [25,34,63]. Cross-disciplinary research, involving dermatology and endocrinology, could offer deeper insights into the systemic and topical effects of vitamin D on skin health. Such an interesting approach may lead to innovations in treating chronic skin conditions, such as psoriasis and atopic dermatitis, while improving general skin vitality and wellness [288,289].

In addition to clinical evaluation, these trials should incorporate patient-reported outcomes and quality of life assessments. Robust clinical data will help advocate for the use of vitamin D in skincare products and guide both consumers and healthcare professionals in making rational decisions. Consumer education is crucial for the successful integration of vitamin D into cosmeceuticals. Prospective investigations ought to concentrate on strategies aiming to augment consumers’ comprehension of the benefits and constraints of vitamin D in skincare. This entails developing educational campaigns that define the differences between systemic and topical vitamin D, as well as establishing reasonable performance standards for such products. Educating consumers about proper usage, possible interactions with other products, and the significance of a thorough skincare routine is believed to be a major key in integrating vitamin D in the cosmetic, cosmeceutical, and nutricosmetic field [283]. Furthermore, future vitamin D-based cosmetics can involve the exploration of plant-derived precursors or lab-synthesized alternatives, which could ensure that such products align with vegan, cruelty-free, and environmentally sustainable practices [290,291]. Finally, as vitamin D applications in cosmetics and nutricosmetics expand, global regulatory alignment, ensuring consistent guidelines and transparency in product labeling for its safe and effective use across regions, will be crucial [290,291].

Ultimately, the future of vitamin D in cosmetics or cosmeceuticals holds significant promise, but advancing in this field requires addressing several key research and development areas. Enhancing formulation techniques, improving bioavailability, understanding molecular mechanisms of action, ensuring safety, exploring innovative delivery systems, investigating personalized skincare solutions, expanding clinical evidence, and even addressing consumer education are all critical aspects to advancing vitamin D’s role in skincare. By tackling these challenges and leveraging new scientific insights, researchers and industry professionals can unlock vitamin D’s full potential in cosmetics, leading mainly to improved skin health and overall wellness [283].

10. Conclusions

Vitamin D has a long history dating back to the 17th century, with its most notable forms being vitamin D₂ and D₃. Vitamin D can be absorbed through the skin in multiple ways, namely penetration through the stratum corneum, diffusion through the epidermis, interaction with keratinocytes, and local metabolism to its active form. Research indicates that topical vitamin D analogs provide great therapeutic benefits, contributing mostly to healthy bones and teeth, immune function, and skin health against diseases like psoriasis. Factors such as UV light exposure and the specific skin type may notably influence vitamin D synthesis in human skin.

A clear relationship indeed exists between vitamin D and skin health. On one hand, the skin serves as a source of vitamin D, and on the other, vitamin D plays an important role in maintaining skin health, with its deficiency leading to dermatological disorders. Preserving optimal vitamin D levels involves multiple factors, and at this point it must be highlighted that sunny climates do not always guarantee sufficient vitamin D production. Based on available research, the supplementation of vitamin D is recommended to maintain normal serum levels and therefore prevent the negative effects of deficiency.

Vitamin D’s confirmed unique anti-inflammatory, anti-melanoma, anti-cancer, anti-UV, anti-aging, and antioxidant properties have ushered the onset of the production of several skincare products, including cosmetic systemic and topical formulations and analogs. This hormone’s astonishing structural, chemical, and biological profile has been extensively exploited against conditions like psoriasis and atopic dermatitis, and less utilized considering vitiligo, acne (vulgaris), and rosacea. Consequently, further research is required to evaluate its role in different skin-related conditions, addressing all arousing controversies and potential positive or side effects, and thus ensuring optimal results in the cosmeceutical field. Vitamin D holds great promise as a natural bioactive constituent, and continuous research and innovation will be essential to unlock its full skincare potential, towards safer, more targeted, and more personalized treatment solutions for a range of dermatological needs and several existent skin types.