Hesperidin from Orange Peel as a Promising Skincare Bioactive: An Overview

The pursuit for better skin health, driven by collective and individual perceptions, has led to the demand for sustainable skincare products. Environmental factors and lifestyle choices can accelerate skin aging, causing issues like inflammation, wrinkles, elasticity loss, hyperpigmentation, and dryness. The skincare industry is innovating to meet consumers’ requests for cleaner and natural options. Simultaneously, environmental issues concerning waste generation have been leading to sustainable strategies based on the circular economy. A noteworthy solution consists of citrus by-product valorization, as such by-products can be used as a source of bioactive molecules. Citrus processing, particularly, generates substantial waste amounts (around 50% of the whole fruit), causing unprecedented environmental burdens. Hesperidin, a flavonoid abundant in orange peels, is considered to hold immense potential for clean skin health product applications due to its antioxidant, anti-inflammatory, and anticarcinogenic properties. This review explores hesperidin extraction and purification methodologies as well as key skincare application areas: (i) antiaging and skin barrier enhancement, (ii) UV radiation-induced damage, (iii) hyperpigmentation and depigmentation conditions, (iv) wound healing, and (v) skin cancer and other cutaneous diseases. This work’s novelty lies in the comprehensive coverage of hesperidin’s promising skincare applications while also demonstrating its potential as a sustainable ingredient from a circular economy approach.


Introduction
Peer and self-perception are concepts that have been playing a major role in our daily life, as a society, throughout time [1].However, in the last few years, most people have been searching for ways to improve their skin and overall appearance in a fast and efficient way due to an increasingly stressful lifestyle while embracing a healthy skin complexion [2].Skin is the largest organ in the human body, being subjected to various external factors and pathogens that can compromise its well-being.Since factors such as sun damage, originating from ultraviolet (UV) radiation; environment pollution; bacteria and fungus; or common daily habits (e.g., poor diet, alcohol ingestion, and smoking) might impair the highly complex cutaneous function, various skincare products (e.g., cosmetics and pharmaceuticals) can be used to minimize or even reverse their effects [3,4].In this way, some of these deleterious factors might accelerate the skin's aging process, which can cause various alterations, such as protein (e.g., elastin and collagen) deterioration by metalloproteinases (MMPs), and the activation of pro-inflammatory cytokines, among other molecular responses, ultimately culminating in the disorganization of the extracellular matrix (ECM); this disorganization can generate skin inflammation, wrinkles, skin elasticity loss, hyperpigmentation, and dehydration, among other issues [3][4][5][6].On the other hand, skincare products can be divided into distinct categories according to their composition, pathway of action, and effects, namely cosmetics, cosmeceuticals, nutricosmetics/nutraceuticals, and skincare pharmaceuticals/therapeutic agents [7,8].Briefly, cosmetics focus mainly the formulation of a high-value product for the skincare industry [17,29] while addressing environmental challenges [14,26].
To the best of our knowledge, there are no reviews that have provided such an extensive overview of the research evolution on hesperidin valorization, extraction, and biological properties, specifically for its application in skincare, within the last 10 years.Therefore, this review aims to outline and offer a new perspective on the research progress regarding hesperidin from citrus agro-food wastes within the last decade and emphasizes particularly the extraction methodologies and biological properties of hesperidin from orange peels as one of the most abundant citrus by-products.Beyond this, the present review explores, in a comprehensive way, the potential of hesperidin as a sustainable bioactive ingredient for vast skincare applications.Hence, the novelty of this work lies not only in the exhaustive coverage of hesperidin's diverse applications in the skincare industry but also in showing the opportunity that the usage of hesperidin represents to transform discarded orange peels into a valuable resource for promoting skin health and well-being.Thus, in an era seeking sustainable solutions, this review highlights environmentally conscious approaches to skincare research based on a circular economy approach.

Research Methodology
In this review, papers on hesperidin from orange peels published in the last decade were obtained through the Web of Science platform, using the keywords "hesperidin", "orange", "extraction", "skin", "aging", "cosmetic", "wound healing" and "skin cancer" while applying the filters for "all databases" and "topic".This approach ensured the inclusion of all articles, review articles, abstracts, clinical trials, and patents available in the databases containing these keywords.
The exclusion criteria for the search were non-English written documents and records that did not analyze the extraction methods from orange peels or study the bioactivities of hesperidin on the skin.

Results
In total, 256 papers resulted from the research conducted by following the parameters described above.However, only 87 papers were carefully selected, taking into consideration the exclusion criteria (Figure 1).The selected papers were separated into three main categories: "Reviews", "Extraction and Purification Methods" and "Biological Activities on Skin".Moreover, the last category was subdivided into different topics to further analyze these subjects, namely "Anti-Aging and Skin's Barrier Improvement", "UVA and UVB Radiation Damage", "Hyperpigmentation and Skin Lightning", "Wound Healing" and "Skin Cancer and Other Cutaneous Diseases" (Figure 2).methods from orange by-products, namely peels, and the application of its functionality to the skin.The papers were analyzed and selected accordingly with the specified criteria.The considered articles were divided into the themes "Reviews", "Extraction and Purification Methods" and "Biological Activities on Skin".The papers were analyzed and selected accordingly with the specified criteria.The considered articles were divided into the themes "Reviews", "Extraction and Purification Methods" and "Biological Activities on Skin".

Figure 1.
Number of papers, from the last decade, related to hesperidin extraction and purification methods from orange by-products, namely peels, and the application of its functionality to the skin.The papers were analyzed and selected accordingly with the specified criteria.The considered articles were divided into the themes "Reviews", "Extraction and Purification Methods" and "Biological Activities on Skin".

Figure 2.
Number of papers related to hesperidin's biological activities on skin from the last decade.
The works that followed under the scope of "Biological Activities on Skin" (previously defined) were subdivided into "Anti-Aging and Skin's Barrier Improvement", "UVA and UVB Radiation Damage", "Hyperpigmentation and Skin Lightning", "Wound Healing" and "Skin Cancer and Other Cutaneous Diseases".

Hesperidin Extraction and Purification from Oranges' Peel Waste
Diverse extraction and purification methods have been described for obtaining hesperidin extracts (Figure 3).For any type of compound intended to be applied in the healthcare and wellbeing industry, namely in the skincare field, its safety and non-toxic nature need to be guaranteed [30].Therefore, well-thought-out optimal methods need to be chosen, depending on the final extract application [28].
To improve the yield of phenolic compounds, some supplementary steps can be added before extraction (pre-treatment).A common procedure is the drying of the orange peels [3,31], which allows a faster extraction process [32].Another described approach is fermentation, aiming to increase the quantity of orange peel secondary metabolites, including polyphenols such as hesperidin, and decrease sugar content [33,34].This methodology has been reported by Kyung and colleagues [35], who applied sugars, lactic acid bacteria, or even mushroom mycelium to ferment Rutaceae fruit extracts.Complementary extraction methods also tested include alkaline treatment, which removes the pectin within the extract by making it insoluble [28], facilitating extract purification later on; the  The works that followed under the scope of "Biological Activities on Skin" (previously defined) were subdivided into "Anti-Aging and Skin's Barrier Improvement", "UVA and UVB Radiation Damage", "Hyperpigmentation and Skin Lightning", "Wound Healing" and "Skin Cancer and Other Cutaneous Diseases".

Hesperidin Extraction and Purification from Oranges' Peel Waste
Diverse extraction and purification methods have been described for obtaining hesperidin extracts (Figure 3).For any type of compound intended to be applied in the healthcare and wellbeing industry, namely in the skincare field, its safety and non-toxic nature need to be guaranteed [30].Therefore, well-thought-out optimal methods need to be chosen, depending on the final extract application [28].
To improve the yield of phenolic compounds, some supplementary steps can be added before extraction (pre-treatment).A common procedure is the drying of the orange peels [3,31], which allows a faster extraction process [32].Another described approach is fermentation, aiming to increase the quantity of orange peel secondary metabolites, including polyphenols such as hesperidin, and decrease sugar content [33,34].This methodology has been reported by Kyung and colleagues [35], who applied sugars, lactic acid bacteria, or even mushroom mycelium to ferment Rutaceae fruit extracts.Complementary extraction methods also tested include alkaline treatment, which removes the pectin within the extract by making it insoluble [28], facilitating extract purification later on; the application of a pulsed electric field for overall improvement in hesperidin's yield and enhancement of biological properties (e.g., antioxidant capacity) [36]; and the instant controlled drop method, allowing easier accessibility to biomolecules in the proper extraction step [37].Following pre-treatment completion, it is common to subject the samples to grinding and homogenization, which are often achieved through freeze-drying [38][39][40][41].
Regarding the extraction process itself, the recovery of flavonoids from agro-food byproducts is usually accomplished through solid-liquid extraction.This process is typically carried out by using organic compounds, such as ethanol and methanol solutions, to obtain the extracts [18,42].The obtention of flavonoids, namely hesperidin, through water extraction has also been reported by some studies [43].However, considering the poor solubility of hesperidin in water (yield around 7.06%) [44], ethanolic extracts are claimed to yield higher quantities (around 40%) [28,45].Nonetheless, processes based on green chemistry have been emerging.This technology is considered valuable since it allows the reduction in energy and additives usage, holds less complex operating conditions, and is easier to scale up [18].In this way, methods such as pressurized liquid extraction [46,47], water bath and ultrasound-assisted extractions [48][49][50][51], hydrodynamic cavitation [52], steam explosion followed by water extraction [53] and subcritical water extraction [38,54], among others (Figure 3), do not require the application of volatile organic solvents.Other commonly used methods, which are being replaced by more advanced and efficient procedures, include maceration [55], Soxhlet-mediated extraction [56,57], and enzymatic extraction.The latter was tested by Madeira and colleagues [58], who specifically applied cellulase, pectinase, and tannase to carry out the process.In addition, alternatives like solid-phase extraction can also be applied to obtain hesperidin-rich extracts [38].
Moreover, some aspects that can be targeted for optimization, as they are reported to have a high impact on the final hesperidin yield, include the solvent type, the sample-tosolvent ratio [38,59], time, pH, and temperature conditions of the process [60,61].
Considering the isolation and purification of the extracts, several methods can be applied to obtain the aimed compound, hesperidin.For this purpose, centrifugation [62], membrane filtration technology [18], acid precipitation [63,64], and high-performance liquid chromatography (HPLC) [28] are examples of methods that can be used for the isolation and purification of hesperidin.Zhang and colleagues [65] used an evaporation technique to concentrate the obtained extracts' pellets after centrifugation; then, they resuspended them to apply different solvents, obtaining three distinct fractions.This type of procedure might be useful to further improve the purity of the final product.
After the isolation and purification steps, techniques such as evaporation and freezedrying, for instance, can be used to concentrate and preserve hesperidin [39,44,66].Additionally, the main techniques usually applied for its detection and relative quantification are HPLC, UV-VIS, Fourier transform infrared spectroscopy (FT-IR), mass spectroscopy, and 1H nuclear magnetic resonance spectroscopy (1H-NMR) analysis [28,38,65].
to yield higher quantities (around 40%) [28,45].Nonetheless, processes based on green chemistry have been emerging.This technology is considered valuable since it allows the reduction in energy and additives usage, holds less complex operating conditions, and is easier to scale up [18].In this way, methods such as pressurized liquid extraction [46,47], water bath and ultrasound-assisted extractions [48][49][50][51], hydrodynamic cavitation [52], steam explosion followed by water extraction [53] and subcritical water extraction [38,54], among others (Figure 3), do not require the application of volatile organic solvents.Other commonly used methods, which are being replaced by more advanced and efficient procedures, include maceration [55], Soxhlet-mediated extraction [56,57], and enzymatic extraction.The latter was tested by Madeira and colleagues [58], who specifically applied cellulase, pectinase, and tannase to carry out the process.In addition, alternatives like solid-phase extraction can also be applied to obtain hesperidin-rich extracts [38].
Moreover, some aspects that can be targeted for optimization, as they are reported to have a high impact on the final hesperidin yield, include the solvent type, the sample-tosolvent ratio [38,59], time, pH, and temperature conditions of the process [60,61].
Considering the isolation and purification of the extracts, several methods can be applied to obtain the aimed compound, hesperidin.For this purpose, centrifugation [62], membrane filtration technology [18], acid precipitation [63,64], and high-performance liquid chromatography (HPLC) [28] are examples of methods that can be used for the isolation and purification of hesperidin.Zhang and colleagues [65] used an evaporation technique to concentrate the obtained extracts' pellets after centrifugation; then, they resuspended them to apply different solvents, obtaining three distinct fractions.This type of procedure might be useful to further improve the purity of the final product.

Application of Hesperidin's Biological Activities on Skincare
Hesperidin has been reported to present various biological activities with the potential to be applied in the skincare field, either in a cosmetic, cosmeceutical [72], or pharmaceutical/therapeutical context [73], as it shows a considerable number of characteristics that can work toward skin improvement [38,74].The chemical composition of the flavonoids might vary on hydroxylation and polymerization degree, substitutions, and conjugations [38].Additionally, the molecular weight of hesperidin is 610.57g/mol, with its melting temperature being around 255 • C. It is also claimed that hesperidin can maintain its stability for up to two years when stored at −20 • C [4].Hence, hesperidin holds a unique structure that allows this compound to have several cutaneous pathways of action, enabling it to target multiple skin issues [38].
Despite all the potential bioactivities of hesperidin for skincare, its formulation continues to represent a challenge due to its solubility constraints.The main problems include the poor solubility of hesperidin in water and its low lipophilic character, which leads to reduced skin absorption [22].However, new technologies have been developed aiming to overcome this issue.
Therefore, this section has the objective to review, in detail, the bioactivities reported from hesperidin, specifically the one from oranges' peels, and its proposed potential application within the skincare field.This includes the levels of hesperidin, assays, testing models, bioavailability assessments, and formulation techniques that have been used along with some molecular mechanisms that can be regulated by this flavone on the skin.

Antiaging and Skin's Barrier Improvement
Intrinsic skin aging is a natural process influenced by numerous endogenous and exogenous factors.Although inevitable, the process of skin aging can lead to a certain level of discomfort due to skin dehydration and roughness.Moreover, concerning aesthetics, signs of skin aging might have a negative impact on people's self-image [75,76].In this way, the development and usage of skincare products containing compounds capable of targeting those inherent aging signs, such as the formation of wrinkles, laxity, dryness, or atypical pigmentation alterations, might be helpful [77].
Considering intrinsic factors, the concepts of aging and oxidative stress have always been interconnected [3].The aging of cutaneous tissue involves the degradation of its ECM by MMPs, among other enzymes (e.g., elastase) [3,78,79].MMPs normally contribute to the natural remodulation of ECM; however, when overexpressed, they promote skin damage and accelerate the skin aging process.ECM degradation includes several alterations, such as loss of skin proteins (mainly collagen and elastin) and reactive oxygen species (ROS) production, leading to DNA and mitochondrial damage, as well as lipid peroxidation [3,6,75,78,80].ROS can also alter skin structure by breaking cell adhesion and the basement membrane structure.All these alterations can compromise the skin barrier, leading to moisture loss [79].Logically, compounds that can target any of these molecular mechanisms have the potential to delay skin aging either through the regulation of various intracellular pathways or by direct improvement of the skin's barrier.For instance, it was described that hesperidin can target MMPs by instigating the expression of metalloproteinase tissue inhibitors (TIMPs).Furthermore, hesperidin can present a protective activity against ROS through direct interaction by inducing the activation of antioxidant enzymes or even by oxidase inhibition [63].
As mentioned before, various external factors can also be involved in the aging process of human skin, one of them being the environment.Highly polluted environments subject the skin barrier to stressing conditions [81].Fernando and colleagues [81] described the effects of particulate matter, a group of liquid and solid atmospheric compounds, on the skin.According to their findings, these compounds damage the skin by inducing senescence and inflammation by producing ROS and triggering apoptosis [81].
Since hesperidin is a flavonoid, it is claimed to possess antioxidant activity [56].In this way, hesperidin acts as a scavenger against ROS, such as 2,2-diphenyl-1-picrylhydrazyl-hydrate (DPPH) and 2,2 ′ -azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) free radicals [35,82].This activity is related to the releasing of protons from this flavone, modulating the radicals' synthesis toward the hesperidin structure [27,38].Furthermore, it was suggested by Baker and colleagues [27] that this is regulated through the ERK/Nrf 2 signaling pathway.Other examples of activities of hesperidin from orange peels that can counteract skin aging and that can be incorporated into cosmetic or cosmeceutical formulations are typified in Table 1.
Regarding hesperidin formulations within an antiaging context, it was reported that its combination with topical clobetasol can be beneficial to restore skin barrier functions [83], which may also be related to the Nrf2 pathway [84,85].
Skin photoaging promoted by ultraviolet (UV) radiation is also a relevant and highly researched topic related to skin aging [12].Therefore, the effects of hesperidin on overcoming the consequences of skin exposure to UV radiation are described in depth further ahead.HDFs-Human Dermal Fibroblasts; FTS-Full Thickness Skin models; HaCaT-Adult Human Keratinocyte; PM2.5-Particulate Matter with an aerodynamic diameter less than 2.5 µm, studied as an air-pollutant testing model; N/A-Non-Added.

UVA and UVB Radiation-Induced Skin Damage
Sun damage, caused by regular sun exposure, is the main catalyst of premature skin aging, inducing a condition known as "skin's photoaging" [75,88].This phenomenon is mediated by UV radiation, which can be divided into ultraviolet A (UVA), ultraviolet B (UVB), and ultraviolet C (UVC) rays.The main components of UV radiation that reach and negatively affect skin are the UVA and UVB radiations.The characteristic wavelength range of each of these components is 320-400 nm (UVA) and 280-320 nm (UVB).For instance, skin disorders such as inflammation and erythema can be caused by chronic exposure to UV rays [75].Additionally, photoaging is related to abnormal epidermal thickness and overall connective tissue disorganization [78,79].On a cellular level, solar radiation might induce apoptosis and generate intra-and/or extracellular ROS, both leading to DNA damage [75,78].In particular, excessive ROS production led by UVB can disrupt cellular equilibrium by increasing oxidative stress and causing several negative alterations, such as protein carbonylation, besides the aforementioned alterations [75].
In the same way that hesperidin from orange peels is characterized as a compound with multifaceted activities for targeting skin aging, it is also a promising molecule to counteract sun damage within this tissue [89].Therefore, among other modes of action (Table 2), it is claimed that hesperidin can restrain UV effects by reducing epidermal thickening, by regulating the expression of angiogenesis-related factors (e.g., PI3K/Akt, VEGF, HIF-1α, and MMPs), by modulating apoptotic proteins induced by oxidative stress, and by regulating some immune cells and inflammatory cytokines, contributing to decreased inflammation [75,[88][89][90].Furthermore, Lacatusu and coworkers [91] stated that topical hydrogels formulated with nano-lipid carriers (NLCs), loaded with hesperidin, showed a remarkable photoprotective effect by absorbing 99% of UVB and 83% of UVA radiation.Hence, hesperidin might be a suitable sunscreen ingredient, for instance, when incorporated into cosmetic or cosmeceutical formulations aiming to target UVA and UVB radiation-induced skin damage (Table 2) [88].HaCaT-Adult Human Keratinocyte; HDFs-Human Dermal Fibroblasts; HEKs-Human Epidermal Keratinocytes; NLCs-Nanostructured Lipid Carriers; N/A-Non-Added.

Skin's Hyperpigmentation and Depigmentation Conditions
Skin conditions that imply the alteration of the natural individual's skin color can be suggestive of a hyperpigmentary disorder, such as melasma or solar lentigo, or even depigmentary autoimmune diseases, such as vitiligo [66,82,94].Moreover, since these disorders are highly perceptible, they can represent a source of low self-esteem and discomfort to the patients.
Melanin is the molecule that defines the color of hair and skin in humans while holding an important protective effect against UV light and ROS [66,82].In general, skin hyperpigmentation-related disorders occur upon an increase in melanin synthesis, also known as melanogenesis, or in its delivery, which happens in the melanosomes.Melanosomes are the organelles responsible for melanogenesis and for the packing of melanin in melanocytes, which are then transferred to keratinocytes [66,72].Melanogenesis, itself, is regulated by numerous inner molecular (e.g., tyrosinase) and environmental (e.g., UV rays) factors.Tyrosinase and microphthalmia-associated transcription factor (MITF), for instance, hold major roles in melanogenesis [82].Therefore, the downregulation of these molecules has been suggested as a target for melanin regulation in hyperpigmentary conditions [66,82].On the contrary, the suppression of factors such as the melanocyte-stimulating hormone (MSH) or oxidative stress can lead to depigmentation, causing depigmentary skin conditions [94].Overall, melanogenesis has been studied to treat hyperpigmentation-and depigmentation-related diseases, leading to the development of products to target these issues [82].
The understanding and modulating of the skin pigmentation process have been attracting interest for a long time regarding skincare industrial applications [72].Thus, it is crucial to find new molecules that can work toward these objectives by regulating melanogenesis and that can be successfully incorporated into novel skincare formulations.
Hesperidin from orange peels, as an antioxidant molecule, has shown both antimelanogenic and melanogenic activities (Table 3), depending on its application, by interacting with different melanogenic intermediates [45,82,94].In the case of hesperidin, it was demonstrated that it can inhibit melanosome transport by blocking the Rab27Amelanophilin, which is a protein complex that takes part in this pathway, on mammalian epidermal melanocytes [72,82].Hesperidin can also downregulate the MITF protein, by activation of the MEK/ErK1/2 pathway, leading to low tyrosinase levels, which ends up in the reduction in melanin production [82].On the other hand, flavonoids can also work to induce topical re-pigmentation when formulated properly.This can be particularly useful in the case of diseases such as vitiligo by hesperidin's immunomodulation.Despite the mechanism not being well understood, Shivasaraun and colleagues [94] suggested that the combination of flavonoids, such as hesperidin, with trimethylpsoralen, in a nanoemulsion-based gel formulation, can improve the treatment of vitiligo.Therefore, hesperidin might be a useful ingredient to be applied either in skin lighting or re-pigmentation products for cosmetic and cosmeceutical purposes.

Wound Healing
Chronic wounds such as ulcers and burns are conditions that require long periods of time to heal (usually over three months) or that may never heal completely due to the interruption of the natural wound-healing process, which is kept at the inflammatory stage.These kinds of wounds are often caused by the patient's inefficient immunity system, which is usually linked to some type of disease (e.g., diabetes), infection, or metabolic deficiency, affecting the individual's quality of life [95][96][97].In this type of wound, the excessive production of edema exudate is common.Exudate overproduction can lead to damage to healthy skin around the wound and can potentiate delayed healing by keeping the wound in the inflammation stage for long periods of time [96,97].This happens due to an abnormal expression of growth factors, TIMPs, and MMPs, as well as impaired integrins' regulation, and ROS formation.These alterations end up affecting the activity and differentiation of fibroblasts and keratinocytes, preventing the formation of a stable ECM [98].Furthermore, these types of wounds can lead to more serious issues like hemorrhages, severe infections, or even gangrene.In this way, chronic wounds deserve further attention, since they represent a major healthcare problem around the world [99].
Wound healing is a complex and dynamic process that is necessary for the recovery and renewal of skin after any type of damage (chemical or physical) [98].Overall, this process can be divided into three stages, namely: (i) inflammation and hemostasis; (ii) proliferation with ECM deposition; and (iii) re-epithelization with tissue remodeling [96].Since it is an extremely intricate process, many types of factors, enzymes, and cells are involved in wound healing [97].
In addition to the above-mentioned biological features, flavonoids like hesperidin extracted from orange peels also exhibit anti-inflammatory and antibacterial properties (Table 4), indicating that it can act as a therapeutic molecule, and it holds the potential to be incorporated into skincare pharmaceuticals [80,95,100].Regarding wound healing, some studies have been carried out to understand hesperidin's mechanisms of action.Some of the proposed mechanisms are related to free radicals scavenging, pro-inflammatory cytokines (e.g., IL-1β, IL-8, and TNF-α) suppression, and enhancement of cell division in fibroblasts [95].Formulation-wise, Bagher and colleagues [95] described that in an in vivo injured skin model, hesperidin-loaded alginate/chitosan hydrogel helped to enhance and accelerate wound healing.Concerning hesperidin's bioactivities, those results were achieved by epithelialization stimulation, the deposition of ECM components, and cellular proliferation [95].Sujitha et al. [101] also recognized that hesperidin nanoemulgel holds ideal characteristics to be applied as a topical drug delivery system.Moreover, hesperidin in wounds from diabetes-induced rats showed promising effects, which might be due to angiogenesis modulation via VEGF-c, Smad-2/3 mRNA, and Ang-1/Tie-2 expression [102].
Hence, hesperidin formulations and scaffolds present potential to be applied in the wound healing and skincare therapeutics fields.

Skin Cancer and Other Cutaneous Diseases
Skin cancer is one of the most prevalent cancers in the human population, particularly in fair-skinned individuals.The frequency of cutaneous cancer has been increasing, and they can be divided into different types according to their primary site on the skin (e.g., melanoma, basal cell carcinoma) [73,113,114].Research related to the development of drugs to treat skin cancer is focused on specific factors and cellular mechanisms, such as DNA damage targeting, apoptosis, and restraining the proliferation of cancerous cells, as well as reducing the increased angiogenesis, which is typical of the carcinogenesis process [73,89,115].Consequently, new innovative treatments based on natural compounds have been explored [73].
Kouassi et al. [12] described that polyphenols can act against skin cancer.Flavonoids, such as hesperidin from citrus fruits (Table 5), are among the natural molecules that present antitumoral activity [75,91].Moreover, it is believed that this flavone might target skin carcinogenesis through ROS scavenging by provoking alterations in the mitochondrial membrane's potential and eventually causing cell necrosis in cancerous cells [72,73,116].For instance, Zhao and colleagues [73] studied the effect of hesperidin in A431 cells (a skin cancer cell line), where they observed that after exposure to the flavone, the cell cycle is arrested in the S phase, which is proposed to be mediated by its downregulation of cyclin D, CD1K2, and thymidylate synthase.Moreover, they reported the change in Apf-1 caspase-3, caspase-8, and PARP protein expression after hesperidin treatment.Furthermore, Li et al. [115] stated that hesperidin reduced the increased tumor cell proliferation by disturbing aerobic respiration in a time-and dose-dependent manner.
Apart from skin cancer, other relevant skin diseases affect the human population.Conditions such as rosacea, psoriasis, and atopic dermatitis, among others, are highly impactful in patients' daily life [89,117,118].
In this way, hesperidin has also been claimed to have a positive impact in helping ameliorate those conditions as a therapeutic agent (Table 5).For example, rosacea and psoriasis are characterized by an increased angiogenesis rate that, as mentioned before, can be inhibited by hesperidin through the regulation of factors such as the PI3K/Akt signaling pathway, VEGF and HIF-1α [89,117].Furthermore, Gupta et al. [119] and Nagashio et al. [118] demonstrated some beneficial therapeutic features for the skin with orally administered hesperidin.Moreover, these studies demonstrated that the oral intake of hesperidin helped to treat pigmented purpuric dermatosis lesions in a human case report [119] and to treat atopic dermatitis in an animal testing model [118].Additionally, hesperidin was suggested to regulate hair follicle growth in androgenetic alopecia, which is achieved through the phosphorylation of Src, Akt, and AMP kinase, and by NO release in the skin.These molecular interactions result in vasculature regrowth, leading to the growth of the hair follicle [120].
Thus, hesperidin seems to hold major potential for skin cancer and disease treatment and might be useful for skincare pharmaceutical therapies incorporation, leading to promising results when combined with pre-established or new treatments, in order to maximize its bioactivities potential.HCT-116-colorectal adenocarcinoma cell line.MCF-7-mammary adenocarcinoma cell line.HepG2-hepatocellular carcinoma cell line.A431-epidermoid carcinoma cell line.A375/CHL01/SKMEL147-human melanoma cell lines; N/A-non-added.

Concluding Remarks
This review critically examined research conducted on hesperidin extracted from orange peels, a by-product of agro-food waste, between the years 2012 and 2022.Within this topic, the present work aimed to focus on the extraction methods of hesperidin, as well as on its bioactivities, with a view to potential industrial applications in skincare.The studies on the orange peels originating from the waste of the agro-food industry brought attention to the benefits of giving a "new life" to these by-products as valuable resources for obtaining value-added products, aligning with the principles of the circular economy.In this way, this review aims to provide an overview of the research evolution within this topic and to uncover the innovations made in terms of hesperidin's bioactivities application on the skin and the formulations developed in the last decade.
Between the years of 2012 and 2022, 87 relevant articles were analyzed in depth, with 32 related to the extraction and purification methods of hesperidin from orange peels, 46 focusing on hesperidin's potential bioactivities on the skin, and the remaining being reviews regarding the latter subjects.Moreover, by analyzing the issues related to "Biological Activities on Skin", it is possible to understand specifically the areas where hesperidin has attracted more interest concerning possible skincare applications.Furthermore, an increasing trend can be observed in the number of articles published throughout the years related to this matter.In total, 256 articles were obtained upon the applied search criteria; however, many of them focused either on another type of source besides orange peels or were related to other polyphenols or applications.Therefore, further studies are needed with a focal point on the bioactivities of hesperidin from orange agro-food wastes, particularly orange peels, leading to skin applications.
Another aspect to be mentioned is that despite research efforts to clarify the bioactivities of hesperidin's molecular mechanisms of action, envisaging potential applications, this question remains only partly explored.These assessments are particularly important since this molecule presents remarkable characteristics to be utilized in numerous industrial applications, from food to cosmetics and healthcare fields.Furthermore, hesperidin seems to have the capacity to be eventually incorporated into more complex formulations or even combined with other compounds from agro-food wastes in a way to potentiate its activity.
This review outlines the evolution and current trends of the extraction methods and bioactivities of hesperidin from orange peels obtained during the processing of oranges.Further research regarding this topic can be highly valuable, since it might imply the development of new impactful skincare formulations incorporating hesperidin that can help with the treatment of multiple skin disorders.While exploring and potentiating hesperidin bioactivities, studies under the scope of the present review can implement a reduced waste ethic by the valorization of peels from oranges.

Figure 1 .
Figure1.Number of papers, from the last decade, related to hesperidin extraction and purification methods from orange by-products, namely peels, and the application of its functionality to the skin.The papers were analyzed and selected accordingly with the specified criteria.The considered articles were divided into the themes "Reviews", "Extraction and Purification Methods" and "Biological Activities on Skin".

Figure 1 .
Figure 1.Number of papers, from the last decade, related to hesperidin extraction and purification methods from orange by-products, namely peels, and the application of its functionality to the skin.

Figure 2 .
Figure 2. Number of papers related to hesperidin's biological activities on skin from the last decade.The works that followed under the scope of "Biological Activities on Skin" (previously defined) were subdivided into "Anti-Aging and Skin's Barrier Improvement", "UVA and UVB Radiation Damage", "Hyperpigmentation and Skin Lightning", "Wound Healing" and "Skin Cancer and Other Cutaneous Diseases".

Table 1 .
Biological activities of commercial and orange peel's hesperidin related to skin anti-aging and skin's barrier improvement.

Table 2 .
Biological activities of commercial and orange peel's hesperidin, related to UVA and UVB radiation-induced skin damage.

Table 3 .
Biological activities of commercial and orange peel's hesperidin, related to skin's hyperpigmentation and depigmentation conditions.

Table 4 .
Biological activities of commercial and orange peel's hesperidin related to wound healing potential.

Table 5 .
Biological activities of commercial and orange peel's hesperidin related to skin cancer and other skin diseases.