Abstract
Specialized pro-resolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins, actively terminate inflammation and restore tissue homeostasis. This review addresses how specialized pro-resolving mediators (SPMs) and their omega-3/omega-6 PUFA precursors influence inflammatory pathways, disease mechanisms, and therapeutic potential across major inflammatory skin disorders. MEDLINE/PubMed was searched on 4 October 2025. Eligible studies included experimental, animal, mechanistic human, and interventional research examining SPMs or omega-3/omega-6 fatty acids. Non-English articles, reviews, conference abstracts, and dietary questionnaire–only studies were excluded. Two reviewers independently screened and extracted data. Due to heterogeneity, a narrative synthesis was performed. No formal risk-of-bias assessment was undertaken Of 359 records, 57 studies were included (26 psoriasis, 24 atopic dermatitis, 7 acne; scarce hidradenitis suppurativa data). Preclinical data consistently demonstrated that SPMs modulate key inflammatory pathways, support epithelial repair, and help restore immune balance. Human studies revealed altered cutaneous and systemic lipid mediator profiles—characterized by reduced omega-3–derived SPMs and predominance of omega-6-driven inflammatory mediators—suggesting impaired resolution mechanisms across these disorders. Interventional studies showed that omega-3 supplementation may reduce inflammatory markers, improve barrier function, and alleviate clinical symptoms. Early evidence on SPMs analogues and receptor agonists indicates promising therapeutic potential, but clinical data remain sparse. The body of evidence is limited by scarce human data, small sample sizes, heterogeneous interventions and variable methods. Many studies rely on subjective or non-standardized clinical outcomes, and the predominance of experimental models further limits the translational relevance of current findings. In summary, disturbances in PUFA-derived lipid mediator pathways and insufficient activation of pro-resolving mechanisms may contribute to the persistence of cutaneous inflammation. Omega-3 supplementation and SPMs-based novel therapies therefore represent plausible adjunctive approaches; however, their therapeutic relevance requires confirmation in future mechanistic and clinical studies.
1. Introduction
Historically, the resolution of inflammation was considered a passive process that occurred naturally once pro-inflammatory signals diminished. This long-standing concept was overturned by discoveries at the end of the 20th century, which revealed that inflammation resolution is an active and tightly regulated process initiated within the earliest hours of the inflammatory response [1]. Resolution begins with a granulocyte-initiated biochemical switch that redirects arachidonic acid (AA) metabolism from the production of pro-inflammatory prostaglandins and leukotrienes toward the generation of lipoxins. Lipoxins, together with resolvins, protectins, and maresins, constitute a class of specialized lipid mediators known as specialized pro-resolving mediators (SPMs) [2]. These bioactive lipids are enzymatically synthesized from dietary omega-3 and omega-6 PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and AA [2].
SPMs play a pivotal role in concluding inflammatory responses by restricting neutrophil migration [3], promoting macrophage-mediated clearance of apoptotic cells and debris (efferocytosis) [4], and supporting tissue repair and regeneration—all without impairing host immune defense [5]. SPMs limit neutrophil recruitment by reducing chemotaxis, impairing adhesion to endothelial cells, and restricting migration across vascular and epithelial barriers [6]. Moreover, SPMs consistently boost macrophage efferocytic capacity, as mediators such as resolvin D1 (RvD1) and its aspirin-triggered epimer were found to enhance clearance of apoptotic neutrophils [7], while maresin 1 (MaR1) markedly strengthens both efferocytosis and antibacterial phagocytosis [8]. This improved clearance further amplifies local SPMs generation, reinforcing pro-resolving pathways [9]. SPMs redirect macrophages from pro-inflammatory toward pro-resolving states by promoting reparative gene programs and suppressing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)–driven cytokine production [10]. Growing evidence shows that SPMs modulate macrophage metabolism by promoting oxidative phosphorylation and fatty-acid oxidation, as well as enhancing mitochondrial function, thereby favoring reparative, pro-resolving functions over pro-inflammatory activity [11]. Beyond their established effects on innate immunity, SPMs also influence adaptive immune responses by limiting memory B-cell proliferation and supporting regulatory T-cell activity [12,13]. They can promote Treg differentiation from naive T cells, enhance Treg functional properties, and indirectly favor Treg-mediated suppression of pro-inflammatory T-cell subsets, thereby contributing to the resolution of inflammation and maintenance of immune homeostasis [12,14]. Inadequate production or dysregulation of these mediators can result in incomplete resolution, contributing to the persistence and progression of various chronic inflammatory and autoimmune conditions [5].
Chronic inflammatory skin disorders, including psoriasis, atopic dermatitis (AD), acne vulgaris, and hidradenitis suppurativa (HS), share overlapping pathogenic mechanisms. These include dysregulation of both innate and adaptive immune responses [15,16,17,18], cytokine-driven inflammation [15,18,19,20], excessive keratinocyte activation [21,22,23], and disruption of skin barrier integrity [18,24]. Despite advances in treatment—such as biologic therapies targeting specific cytokines—current strategies largely focus on suppressing inflammation rather than restoring immune balance and physiological resolution. Consequently, there remains a need for approaches that actively promote the natural termination of inflammation while minimizing long-term immunosuppression.
SPMs offer a novel avenue in this regard, as they restore tissue homeostasis without directly inhibiting immune activation. Their biosynthesis from dietary omega-3 and omega-6 fatty acids (FAs) further suggests that nutritional interventions could serve as practical adjuncts for modulating chronic inflammation. Additionally, SPMs levels and their metabolic pathways hold promise as biomarkers for disease activity and therapeutic response, paving the way for more personalized treatment strategies in dermatology.
The present systematic review aims to provide a comprehensive overview of the evidence regarding SPMs and their omega-3/omega-6 FAs precursors in selected inflammatory skin diseases, including psoriasis, AD, acne vulgaris, and HS. Specifically, this work aims to (i) summarize current knowledge on the roles of SPMs in cutaneous inflammation and resolution, (ii) evaluate interventional studies investigating omega-3/omega-6 FAs supplementation, and (iii) explore the translational potential for therapeutic development and biomarker discovery.
2. Materials and Methods
This systematic review was conducted in accordance with the PRISMA 2020 guidelines. To promote transparency, the full study protocol and search strategy have been archived and are publicly available at https://doi.org/10.17605/OSF.IO/FV9PR. Following peer-review suggestions, the protocol was amended to include a narrative synthesis of the data and an assessment of risk of bias for studies included in the synthesis. We systematically searched MEDLINE (via PubMed) on 4 October 2025, using Medical Subject Headings (MeSH) without date restrictions. The objective of this review was to evaluate the available evidence on SPMs and their dietary precursors—omega-3 and omega-6 FAs—with a focus on their role in the pathogenesis and therapeutic potential of inflammatory skin diseases, including psoriasis, AD, acne vulgaris, and HS.
The PubMed search strategy combined terms for inflammatory skin diseases (“Psoriasis”, “Dermatitis, Atopic”, “Acne Vulgaris”, “Hidradenitis Suppurativa”) with terms related to lipid mediators and fatty acids (“Lipoxins”, “Docosahexaenoic Acids”, “Eicosapentaenoic Acid”, “Fatty Acids, Omega-3”, “Fatty Acids, Omega-6”) using the Boolean operator AND. The complete PubMed search string is provided in the Supplementary Material.
All retrieved records were merged, and duplicates were removed. Eligible studies included original experimental, animal, and human studies addressing the role of SPMs, or omega-3/omega-6 FAs in the context of inflammatory skin diseases. Non-English publications, conference abstracts without full text, narrative reviews, editorials, and commentaries were excluded from the analysis. Interventional studies involving omega-fatty acid supplementation as well as observational studies based on objective biochemical measurements of fatty acid profiles were included, while studies relying solely on self-reported dietary intake were excluded.
To achieve a comprehensive understanding of the SPMs system in inflammatory skin diseases, this review integrates evidence from two main streams: (i) studies measuring or directly reporting SPMs (lipoxins, resolvins, protectins, maresins) in humans, animal models, or experimental systems, and (ii) interventional studies involving the administration of long-chain omega-3 FAs (EPA, DHA) on the course of the disease. The collected evidence was synthesized and compared across these two streams using narrative approach to highlight consistent patterns and mechanistic insights.
Titles and abstracts of all retrieved records were independently screened by two reviewers (A.B.-B. and O.J.-Z.), with disagreements resolved by a third reviewer (H.M.). Full-text articles of potentially relevant studies were then assessed for eligibility. Data extraction was performed independently by two reviewers (A.B.-B. and O.J.-Z.) using a standardized form. Extracted information included study design, population, intervention/exposure characteristics, analytical methods, lipid mediator measurements, and clinical outcomes. We extracted all reported outcomes related to SPMs concentrations, omega-3/omega-6 fatty acid profiles, clinical disease severity, and mechanistic inflammatory markers, irrespective of measurement methods or time points. Additional variables included participant characteristics, disease subtype, intervention dose and duration, model system, and analytical methods; missing or unclear information was extracted as reported without assumptions. Due to heterogeneity in study designs, analytical methods, and outcome measures, the results were summarized using a structured narrative synthesis framework, and therefore no effect measures were predefined, nor were reporting bias or certainty assessments performed.
3. Results
The search resulted in the retrieval of 359 records of which 354 were screened for relevance. Seventy-seven full-text articles were assessed for eligibility, and 20 were excluded. The reasons for exclusion were as follows: (1) assessment of omega-3 exposure based exclusively on food frequency questionnaires (n = 6) [25,26,27,28,29,30], nutritional counseling (n = 2) [31,32], or multi-ingredient supplements not specific to omega-3 fatty acids (n = 1) [33]; (2) outcomes unrelated to inflammatory skin diseases (n = 6) [34,35,36,37,38,39]; (4) ineligible study design, including observational studies focused solely on metabolic biomarkers (n = 2) [40,41]; and case report series (n = 1) [42]; and (5) insufficient or missing data on pro-resolving or anti-inflammatory markers (n = 2) [43,44]. Fifty-seven studies were ultimately included in qualitative synthesis.
The flowchart presenting full search strategy is demonstrated in Figure 1.
Figure 1.
PRISMA 2020 flow diagram illustrating the study identification, screening, eligibility assessment, and inclusion process.
The basic characteristics of the original papers on the researched topic are summarized in Table 1, Table 2, Table 3 and Table 4. Each table includes study design, population characteristics, intervention or exposure details, biochemical endpoints related to omega-3 fatty acids or SPMs, and clinical outcomes relevant to inflammatory skin diseases. In total, 21 experimental, 28 human interventional, and 8 human observational studies were identified, including two that combined in vitro and human investigations. Of the 57 studies, the majority focused on psoriasis (n = 26) and atopic dermatitis (n = 24), with a smaller number addressing acne (n = 7). Given the heterogeneity of included studies, which range from in vitro and animal models to mechanistic human investigations and clinical interventions and the focus on mechanistic insights into SPMs and their precursors, a formal risk of bias assessment was not conducted. Results of individual studies are presented narratively in the disease-specific sections and corresponding tables; quantitative effect estimates were inconsistently reported and could not be standardized. No meta-analysis was conducted, and consequently, heterogeneity analyses, sensitivity analyses, reporting bias assessments, and certainty-of-evidence evaluations were not undertaken.
Table 1.
Effects of Specialized Pro-Resolving Lipid Mediators on Psoriasis Pathophysiology.
Table 2.
Clinical and Preclinical Evidence of ω-3 Polyunsaturated Fatty Acids in Psoriasis.
Table 3.
Summary of Clinical, Experimental, and Observational Evidence on Omega-3 Fatty Acids and Specialized Pro-Resolving Mediators in Acne Vulgaris.
Table 4.
Summary of Clinical, Experimental, and Observational Evidence on Omega-3 Fatty Acids and Specialized Pro-Resolving Mediators in Atopic Dermatitis.
3.1. Psoriasis
In total, 26 studies evaluating lipid mediators and omega-3 fatty acids were included in the analysis. Within the first evidence stream, eight studies directly examined SPMs in murine models (n = 6) or human samples (n = 2) (Table 1).
One animal study demonstrated that dietary DHA increased cutaneous levels of several D-series resolvins, protectins, and maresins while simultaneously reducing prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) [50]. The remaining preclinical studies investigated exogenous administration of SPMs or their receptor agonists, consistently showing attenuation of imiquimod-induced psoriasiform dermatitis, decreased epidermal hyperplasia, and suppression of pro-inflammatory cytokines such as IL-6, IL-8, and IL-23, accompanied by inhibition of the IL-23/IL-17 axis, along with downregulation of parallel inflammatory pathways involving signal transducer and activator of transcription 1 (STAT1) and NF-κB [45,46,47,48,49]. Human mechanistic and observational investigations further revealed altered profiles of omega-3– and omega-6–derived lipid mediators in psoriatic lesions compared with nonlesional skin and healthy controls, with lesional–control differences exceeding those observed in blood [51,52].
The second evidence stream predominantly concerned the effects of omega-3 fatty acids on psoriasis (Table 2).
Experimental and preclinical studies in cellular and reconstructed skin models showed that DHA, EPA, α-linolenic acid (ALA), and selective free fatty acid receptor 4 (FFA4) agonists improved keratinocyte differentiation, restored lipid-mediator balance, and reduced TH17/TH1-related cytokines [53,55,56,58]. Two studies examining lipoxin A4 receptor agonists in imiquimod-induced murine models reported divergent clinical outcomes, with one study showing no clinical benefit and the other demonstrating significant improvement in psoriasiform skin inflammation [54,57]. Interventional studies in humans demonstrated heterogeneous but overall beneficial outcomes across topical, oral, and intravenous omega-3 PUFA interventions, including reductions in Psoriasis Area and Severity Index (PASI), improvements in quality-of-life measures, and modulation of inflammatory lipid pathways in selected trials. Topical omega-3 PUFA application showed improvement in treated lesions, though differences versus placebo were generally modest [60,64]. Intravenous omega-3 lipid emulsions were associated with rapid clinical response and increased anti-inflammatory lipid mediators [62,65]. Oral omega-3 supplementation yielded variable outcomes, with most trials reporting improvements in clinical outcomes, including PASI reduction, decreased erythema and scaling, and enhanced quality-of-life scores [59,66,67]. Several studies additionally demonstrated modulation of inflammatory lipid mediators and cytokine profiles, supporting anti-inflammatory effects of omega-3 PUFAs [59,68,69]. However, a large randomized controlled trial of high-dose fish-oil ethyl esters showed no clinical benefit over corn oil despite increased serum omega-3 levels [63]. Finally, Mendelian randomization analysis supported a protective association between genetically predicted omega-3 fatty acid levels and psoriasis risk [70].
The included studies on psoriasis exhibited several sources of bias. Preclinical investigations showed high indirectness due to reliance on imiquimod models or in-vitro keratinocyte systems, which do not fully reflect psoriatic pathogenesis. Human mechanistic studies were constrained by small sample sizes, potential confounding, and low detectability of several SPMs, contributing to measurement bias. Clinical interventions were highly heterogeneous, often lacking detailed randomization, blinding, or preregistered protocols, and showed variable dosing and outcome measures, resulting in high risk of performance, detection, and reporting bias.
3.2. Acne Vulgaris
In total, seven studies evaluated the role of omega-3 and omega-6 fatty acids as well as PUFA-derived lipid mediators in acne vulgaris; however, none of the included studies directly quantified SPM levels (Table 3).
Evidence from preclinical studies demonstrated that omega-3 supplementation reduced inflammation and comedone formation in acne-induced rats, while fecal microbiota transplantation from omega-3-treated donors confirmed a gut–skin axis mechanism [76]. Observational and genetic evidence indicates that acne patients often present with reduced EPA levels and elevated AA/EPA ratios, while Mendelian randomization analysis supports a protective role of EPA and AA, and a risk-enhancing effect of DGLA, implicating fatty acid desaturase 1 (FADS1) and fatty acid desaturase 2 (FADS2) enzymes in acne pathophysiology [73,77]. Within the interventional evidence stream, five studies evaluating omega-3 fatty acid supplementation showed reductions in acne lesion counts, improvements in patient-reported outcomes, or attenuation of isotretinoin-induced adverse effects [71,72,74,75,76]. Mediterranean diet supplemented with algal DHA/EPA improved acne severity and quality-of-life scores in a 16-week study [75]. In general, omega-3 fatty acids appear to exert protective effects in acne, reducing lesion severity and alleviating treatment-related adverse effects during isotretinoin therapy, although the magnitude of effects varies across studies. Additionally, omega-3 supplementation may beneficially modulate the gut microbiome, highlighting potential systemic mechanisms underlying their therapeutic action.
The included acne studies were limited by small sample sizes, indirect preclinical models, and confounding in human studies. Importantly, none of the studies directly quantified SPMs. Interventional trials were heterogeneous in design, dosing, and outcome measures, resulting in moderate-to-high risk of bias across performance, detection, and reporting domains.
3.3. Atopic Dermatitis
As summarized in Table 4, a total of 24 studies addressing AD met the inclusion criteria of this systematic review.
Among these, only two studies directly investigated specialized pro-resolving mediators [79,98]. In preclinical model of AD, intraperitoneal administration of RvE1 attenuated disease severity by suppressing serum IgE, Th1/Th2 cytokine responses, and inflammatory cell infiltration in dose-dependent manner [79]. In interventional human studies, topical application of lipoxin A4 in infants with atopic dermatitis resulted in rapid and clinically significant improvements in erythema, pruritus, and inflammatory skin lesions, with efficacy comparable to that of a topical corticosteroid [98].
Regarding omega—fatty acids, a total of 22 eligible studies were identified, including 6 preclinical investigations in animal models, 4 observational studies in humans, and 12 interventional trials. The latter comprised 1 topical intervention [91], 1 intravenous administration [92], 4 oral omega-3 supplementation studies in patients with atopic dermatitis [89,90,94,101], and 6 prenatal supplementation trials assessing the development of allergic diseases, including atopic dermatitis, in infants [93,95,96,97,99,100].
Across preclinical models of atopic dermatitis, dietary or topical administration of omega-3 fatty acids, including DHA and EPA, generally reduced skin inflammation and disease severity, serum IgE levels, inflammatory cell infiltration, and Th2/Th17-related cytokines, while enhancing regulatory immune responses [78,80,81,82,84]. Several studies also demonstrated suppression of keratinocyte-derived thymic stromal lymphopoietin (TSLP) and partial restoration of epidermal barrier function [78,82], whereas selected models showed changes in lipid mediator profiles without clear clinical improvement [83].
Observational and mechanistic human studies indicate that higher maternal or circulating omega-3 long-chain PUFAs, particularly DHA, are generally associated with a lower risk of atopic dermatitis in infants [85,88], whereas elevated omega-6 levels or a higher omega-6/omega-3 ratio increase disease risk [86,87]. In one study, moderate EPA and DHA were linked to lower risk, while omega-3 PUFAs overall and the omega-6/omega-3 ratio showed no consistent association [87]. In patients with atopic dermatitis, FADS2 activity was elevated, resulting in increased omega-6 PUFA production and decreased omega-3 levels [86].
In interventional studies, topical application of EPA/DHA ointment significantly improved clinical outcomes in patients with AD [91], while intravenous infusion of an omega-3–based lipid emulsion reduced disease severity and increased plasma and membrane EPA levels and the EPA/AA ratio [92]. Among studies investigating oral omega-3 supplementation in patients with AD, results were mixed. Some trials reported significant improvements in patient-reported outcomes [89,101], SCORAD scores [94,101], affected skin area, and immunologic markers [94], while other studies found no significant effect on disease severity, topical steroid use, or clinical symptoms [89,90]. In maternal supplementation studies, omega-3 fatty acid intake during pregnancy generally increased DHA and EPA levels in maternal and cord plasma [96,97]. Effects on infant atopic outcomes varied: some trials reported reduced severity of atopic dermatitis [93], lower overall incidence of AD [97,100], reductions limited to IgE-associated eczema [95], or decreased allergen sensitization [93,95], while others found no significant differences in overall incidence or severity of AD during the first 1–2 years of life [93,96,99].
The included AD studies exhibited multiple sources of bias. Preclinical studies were generally indirect, relying on murine or rat models that may not fully reflect human disease. Sample sizes were small, and outcomes were often surrogate or mechanistic, contributing to indirectness and potential measurement bias. Observational human studies were subject to confounding, and variability in fatty acid assessment methods. Interventional trials varied widely in design, dosing, route of administration, and outcome measures. Only two studies directly assessed SPMs, limiting direct mechanistic evidence in humans. Prenatal supplementation trials were generally well-conducted but heterogeneous in timing, dose, and follow-up duration, leading to variable effects on AD incidence or severity.
3.4. Factors Contributing to Outcome Differences
Heterogeneity across studies was observed for all three disease entities—psoriasis, acne vulgaris, and atopic dermatitis—arising from multiple sources. Preclinical studies varied in model type (murine, rat, or in vitro keratinocyte/skin substitutes), induction method, and outcome assessment, limiting direct translational comparability. Clinical studies differed in population characteristics, intervention type (oral, intravenous, topical), dose, duration, and timing of supplementation. Outcome measures were diverse, including disease severity scores, lesion counts, cytokine profiles, lipid mediator levels, and quality-of-life indices. Methodological differences, such as randomization, blinding, sample size, and follow-up length, further contributed to variability. Collectively, these factors likely explain the observed heterogeneity in intervention effects and highlight the need for standardized protocols in future trials.
4. Discussion
4.1. Biosynthesis of Lipid Mediators
Lipid mediators are a collective term referring to signaling molecules derived from the metabolism of PUFAs, which play a key role in regulating the inflammatory response. This broad category includes both pro-inflammatory and pro-resolving molecules, with the overall control of inflammation depending on the balance between two main enzymatic pathways: the cyclooxygenase (COX) and lipoxygenase (LOX) pathways [102]. In the initial step of the inflammatory response, phospholipase A2 (PLA2) releases PUFAs from membrane phospholipids. These FAs are subsequently metabolized by COX, LOX, and cytochrome P450 enzymes (CYP450) into various classes of lipid mediators. COX metabolizes the omega-6 AA into pro-inflammatory eicosanoids such as prostaglandins and thromboxanes. However, one of the intermediate metabolites can serve as a substrate for 5-lipoxygenase, leading to the production of lipoxins [103].
The primary precursors of most SPMs are the omega-3 FAs EPA and DHA. Through enzymatic processing by the 5-LOX and 12-LOX pathways, EPA is converted into the E-series resolvins (RvE1–RvE4). In contrast, DHA gives rise to the D-series resolvins (RvD1-RvD6), protectins, and maresins—key lipid mediators that collectively promote the resolution phase of inflammation [104]. Figure 2 illustrates the interconnected biosynthetic pathways that generate both pro-inflammatory and pro-resolving mediators PUFAs.
Figure 2.
Biosynthetic Pathways of Pro-Inflammatory and Specialized Pro-Resolving Lipid Mediators Derived from Polyunsaturated Fatty Acids. Abbreviations: AA, arachidonic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; PLA2, phospholipase A2; COX-1/COX-2, cyclooxygenase-1/2; acetyl-COX-2, aspirin-acetylated cyclooxygenase-2; CYP450, cytochrome P450 monooxygenase; LOX, lipoxygenase; 5-LOX/12-LOX/15-LOX, 5-, 12-, or 15-lipoxygenase; PG, prostaglandin; PGE2, prostaglandin E2; TXA2, thromboxane A2; LT, leukotriene; LTA4–LTE4, leukotrienes A4–E4; HEPE, hydroxy-eicosapentaenoic acid; HpEPE, hydroperoxy-eicosapentaenoic acid; RvE1–4, E-series resolvins; RvD1–6, D-series resolvins.
Dietary omega-3 FAs, primarily EPA and DHA, can be incorporated into membrane phospholipids, thereby increasing the pool of substrates available for the synthesis of SPMs. Consequently, a diet enriched in these FAs enhances the body’s capacity to generate such mediators. The beneficial and protective roles of omega-3 FAs in mitigating chronic inflammatory diseases across various organ systems are well established [105]. Nonetheless, despite decades of research, the therapeutic efficacy of omega-3 supplementation remains a matter of debate, as findings from controlled clinical trials have been inconsistent [106,107,108,109]. The identification of SPMs and their specific receptors has created new opportunities for the development of targeted pharmacological interventions that modulate these pathways. This is of particular interest because pro-resolving mechanisms are anticipated to achieve inflammation control with fewer adverse effects compared to conventional anti-inflammatory agents [104].
4.2. Overview of SPMs Classes
SPMs comprise four major families—lipoxins, resolvins, protectins, and maresins [104]. The individual classes of SPMs differ in their functional profiles and timing of action. Each class reaches peak concentrations and displays maximal biological activity at distinct stages of the inflammatory process [104]. Moreover, several SPMs exhibit tissue-specific patterns of distribution, achieving their highest levels in organs characterized by high cellular metabolic activity [110].
The biological effects of SPMs are mediated through binding to specific receptors, enabling precise modulation of cellular responses [111]. Their actions are complementary and occur in a defined chronological sequence, ensuring a smooth transition from the pro-inflammatory phase to the gradual reduction in inflammatory infiltrates and pro-inflammatory mediators, activation of regenerative processes, tissue repair, and ultimately the restoration of homeostasis [104]. These processes are schematically illustrated in Figure 3, which summarizes the key pro-resolving, immunomodulatory, and other actions of SPMs leading to restoration of homeostasis.
Figure 3.
Overview of the pro-resolving and immunomodulatory actions of SPMs, highlighting their roles in resolving inflammation, regulating immune responses, and promoting tissue repair and homeostasis. Abbreviations: SPMs, Specialized Pro-Resolving Mediators; Th1/Th2/Th17, T helper cell subsets type 1, 2, and 17; CD80/CD86, Co-stimulatory molecules expressed on antigen-presenting cells; NRF2, Nuclear Factor Erythroid 2–Related Factor 2; TGF-β, Transforming Growth Factor beta; ECM, Extracellular Matrix; M2, Alternatively activated (anti-inflammatory) macrophage phenotype; ↓, decrease; ↑, increase.
4.2.1. Lipoxins
Lipoxins were the first identified members of the SPMs family [103]. They are produced in multiple tissues via transcellular pathways involving cooperative interactions between migrating polymorphonuclears and epithelial or endothelial cells at the site of inflammation [112]. Lipoxins function predominantly during the early phase of resolution, exerting multiple actions that together promote the termination of inflammation and support tissue homeostasis. Acting primarily through the Lipoxin A4 Receptor/Formyl Peptide Receptor 2 (ALX/FPR2), they limit the production of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α) and IL-1β, and promote epithelial repair together with the restoration of vascular barrier integrity [113]. Lipoxins modulate both innate and adaptive immune responses to facilitate the resolution of inflammation. They reprogram macrophages toward a proresolving, M2-like phenotype, enhancing efferocytosis and activating transcriptional programs that support tissue repair, while simultaneously reducing neutrophil infiltration [114]. Beyond their effects on innate immunity, lipoxins influence adaptive immune cells by regulating B and T cell responses during the post-resolution phase and limiting the proliferation of memory B cells [12,13]. In addition to their immunomodulatory functions, lipoxins limit fibrosis by modulating transforming growth factor-β (TGF-β) signaling, inhibiting fibroblast proliferation, and reducing extracellular matrix deposition, with evidence that they can reverse established fibrotic lesions in experimental models [115]. In addition, they activate cytoprotective antioxidant pathways, including nuclear factor erythroid 2–related factor 2 (NRF2) signaling, thereby protecting tissues from oxidative stress [116]. Taken together, these actions highlight the central role of lipoxins in orchestrating the transition from inflammation to resolution while preserving tissue integrity and promoting repair.
The metabolism of eicosanoids can be modulated by certain pharmacological agents in ways that favor the formation of lipoxins. For instance, aspirin-induced acetylation or statin-mediated nitrosylation of COX-2 can shift the enzyme’s catalytic function from its typical endoperoxidase activity toward a lipoxygenase-like pathway [117,118]. This functional reprogramming promotes the biosynthesis of epimeric molecules, commonly referred to as aspirin-triggered lipoxins (ATLs). The epimers retain the pro-resolving and anti-inflammatory properties characteristic of native lipoxins but exhibits enhanced metabolic stability and resistance to enzymatic degradation [119]. Other strategies for modulating the lipoxin pathway include the use of stable synthetic analogs, receptor-specific agonists targeting ALX/FPR2, and cell-penetrating peptides that influence intracellular G protein–coupled receptor (GPCR) signaling, all of which enhance lipoxin-mediated resolution and provide potential avenues for therapeutic intervention in chronic inflammatory diseases [120,121].
4.2.2. Resolvins
Resolvins constitute a distinct family of SPMs biosynthesized from omega-3 FAs and are categorized into two main series: the E-series (RvE1–RvE4), derived from EPA, and the D-series (RvD1–RvD6), originating from DHA [120,122,123]. Biologically, resolvins differ from lipoxins in several key aspects. Unlike lipoxins, which act primarily by limiting neutrophil infiltration, resolvins exert broader actions across immune, vascular, and neural systems [120]. They not only dampen inflammation but also actively promote tissue repair, angiogenesis, and neuroprotection, functioning at picomolar to nanomolar concentrations. Aspirin-triggered (AT) epimers, such as AT-RvD1 and AT-RvD3, are generated via acetylation of COX-2 by aspirin, which redirects biosynthetic pathways toward pro-resolving mediators [124,125]. Although resolvins generally signal through distinct receptors, not all have fully characterized binding partners. Some can engage receptors shared with lipoxins, interacting with alternative binding sites and functioning as biased agonists, thereby eliciting divergent intracellular signaling pathways [126]. Collectively, these account for their therapeutic potential in chronic inflammatory diseases, infections, asthma, atherosclerosis, and neurodegenerative disorders.
4.2.3. Protectins
Protectin D1 (PD1), also known as neuroprotectin D1 (NPD1) in neural tissues, is a DHA–derived SPM whose actions depend on tissue context and cell type [127]. In the nervous system, NPD1 promotes neuronal survival by counteracting oxidative stress and enhancing apoptosis [127]. Outside the nervous system, PD1 functions as an immunoresolvent, limiting cytokine release, reducing neutrophil infiltration, and promoting macrophage-mediated clearance [127]. It also exhibits antiviral activity and contributes to tissue repair [128]. The dual capacity of PD1 to suppress inflammation while enhancing cell survival highlights its relevance as a potential therapeutic mediator in neurodegenerative, retinal, and ischemic pathologies.
4.2.4. Maresins
Maresins are SPMs derived from DHA, possessing both anti-inflammatory and pro-resolving properties. The group comprises three primary forms: maresin 1 (MaR1), maresin 2 (MaR2), and maresin conjugates in tissue regeneration (MCTR) [129]. These mediators are produced by 12-LOX in macrophages and dendritic cells, where they promote efferocytosis and facilitate the resolution of inflammation. Maresins also suppress the expression of pro-inflammatory cytokines and limit polymorphonuclear leukocyte infiltration [130]. Notably, unlike other classes of pro-resolving mediators, maresins exhibit analgesic effects [131], highlighting their unique role in both inflammation resolution and pain modulation.
4.3. Lipids as a Structural and Bioactive Regulators of Cutaneous Homeostasis
The skin is a lipid-rich organ, and its barrier function critically depends on the composition of PUFAs [132]. Both omega-3 and omega-6 PUFAs are integral components of epidermal phospholipids and ceramides. Omega-6 PUFAs, particularly linoleic acid, facilitate ceramide synthesis, thereby enhancing barrier function and reducing transepidermal water loss (TEWL) [133], whereas omega-3 PUFAs exhibit anti-inflammatory and antioxidant properties, modulating cutaneous immune responses and protecting against environmental stressors such as UV radiation and pollution [134,135]. Beyond structural roles, these FAs serve as precursors for a diverse array of bioactive lipid mediators, including SPMs [2].
Dysregulation of PUFAs metabolism and chronic inflammation are central features in the pathogenesis of persistent dermatological conditions, including AD, psoriasis, and acne [56,136,137]. Altered ratios of omega-6 to omega-3 PUFAs can exacerbate pro-inflammatory signaling, leading to sustained epidermal barrier dysfunction, increased TEWL, and heightened susceptibility to environmental insults [138,139]. Moreover, chronic inflammatory states are often accompanied by disturbances in lipid homeostasis, including impaired ceramide synthesis and altered phospholipid composition, which further compromise barrier integrity and skin hydration [140]. These observations have stimulated increasing interest in dietary interventions as modulators of disease course, with omega-3 PUFAs supplementation demonstrating benefits in reducing inflammatory markers, restoring lipid balance, and improving clinical outcomes in chronic inflammatory skin disorders [58,67]. Enhanced availability of omega-3 PUFAs facilitates the enzymatic conversion of EPA and DHA into their respective SPMs families, thereby augmenting the intrinsic capacity of the host to generate pro-resolving lipid mediators [141,142]. Accumulating evidence shows that omega-3 PUFAs can also directly modulate immune regulation by promoting expansion and functional activity of Tregs, shifting immune balance toward resolution rather than inflammation. For instance, in a murine model of atopic dermatitis, administration of DHA enhanced the generation of CD4+Foxp3+ Tregs and increased anti-inflammatory IL-10/TGF-β signaling, reducing skin inflammation [80]. Another example comes from a 3D psoriatic skin model, where EPA treatment decreased IL-17A–secreting T cells and increased FOXP3+ Treg populations, resulting in normalized keratinocyte proliferation and reduced inflammatory mediator levels [58]. Consequently, an increased dietary or systemic supply of omega-3 FAs serves not only as the substrate pool but also promotes the biochemical milieu favorable for the resolution of inflammation. Targeting PUFAs composition through nutrition represents a promising adjunct strategy for managing chronic skin diseases by addressing both inflammation and lipid metabolic imbalance.
4.4. Psoriasis
4.4.1. Lipid Dysregulation in Psoriasis
Psoriasis is widely recognized as a disease predominantly driven by Th1/Th17 immune responses, with elevated levels of cytokines such as IL-17A, IL-17F, IL-22, IL-23, TNF-α, and IFN-γ playing central roles in its pathogenesis [143]. While traditionally considered an immune-mediated disorder developing in genetically predisposed host, increasing evidence highlights a crucial contribution of lipid metabolism to its pathogenesis. Psoriatic skin exhibits altered lipid composition, including disturbed levels of ceramides, free FAs, and eicosanoids, which can impair barrier integrity and amplify inflammatory cascades through the AA and prostaglandin pathways [51,140]. Genes involved in lipid metabolism, such as PLA2G4E, ELOVL, and FABP family members, have been shown to be dysregulated in psoriatic skin, indicating that altered lipid processing may play a role in disease pathogenesis [140,144,145]. These genetic variations may alter the synthesis or turnover of structural and signaling lipids, thereby facilitating immune activation and perpetuating chronic inflammation. Recent research has provided evidence that higher genetically predicted omega-3 FAs levels are associated with a reduced risk of psoriasis, thereby strengthening the evidence that omega-3 FAs may play a direct, biologically meaningful role in modulating psoriasis susceptibility [70]. Thus, the interplay between genetic predisposition and lipid dysregulation represents a key but still incompletely understood component of psoriasis pathogenesis.
These genetic and metabolic disturbances are reflected in a distinct lipidomic profile observed in individuals with psoriasis, characterized by an imbalance between unsaturated FAs classes [146]. The observed shift toward a higher proportion of monounsaturated species suggests altered desaturase activity and disrupted metabolic regulation, while the concurrent reduction in polyunsaturated fractions and a distorted omega-6 to omega-3 equilibrium may contribute to the pro-inflammatory milieu typical of psoriasis. Current evidence indicates that patients with psoriasis display decreased levels of omega-3 PUFAs and elevated omega-6 FAs in both serum and erythrocyte membranes, correlating with higher inflammatory markers such as C-reactive protein (CRP) and IL-6, as well as greater disease severity [146,147]. Studies also suggest that an increased omega-6/omega-3 ratio and elevated saturated FAs content may promote systemic inflammation, metabolic disturbances, and comorbidities including obesity, hepatic dysfunction, and cardiovascular risk [147,148].
4.4.2. Evidence for Omega-3 Fatty Acids Supplementation
Investigations into the therapeutic potential of omega-3 FAs supplementation, including topical applications, in psoriasis began in the late 1980s [59,60]. Early studies demonstrated encouraging outcomes in small patient cohorts; however, these findings were subsequently scrutinized, partly due to the lack of double-blind study designs. In the following decades, further evidence emerged from randomized, double-blind trials; however, the findings remained heterogeneous, primarily due to variations in dosage, study duration, and selected clinical endpoints. Two small studies evaluating the efficacy of a topical formulation containing omega-3 FAs were conducted in comparison with a placebo cream, applied simultaneously to matched lesions within the same patients [60,64]. The first report, involving a cohort of 11 patients with psoriasis, demonstrated objective improvement and suggested the superiority of the omega-3 cream over the placebo [60]. However, a subsequent larger, multicenter study found that general improvement occurred with both formulations, but neither formulation was significantly more effective than the other [64]. The vast majority of available data come from clinical trials investigating the impact of oral supplementation with omega-3 FAs on the course of psoriasis. Most studies demonstrated a generally positive effect on disease activity and associated symptoms, including pruritus; however, differences were not always statistically significant when assessed using objective measures such as the PASI score [67,68]. Interpretation of these results is challenging due to the heterogeneity of study designs, with dosages ranging from 2.6 to 3.6 g/day of EPA ± DHA and treatment durations from 12 weeks to 12 months [61,67]. According to the findings reported by Petrovic et al. [69], the beneficial effect of omega-3 PUFAs supplementation in plaque psoriasis appears to be mediated by anti-inflammatory mechanisms, as evidenced by alterations in immune cell populations and cytokine profiles that correlated with clinical improvement. Notably, two studies assessed the effects of intravenous monotherapy with omega-3–enriched lipid emulsions in comparison to omega-6–based formulations [62,65]. Both studies reported a significant reduction in PASI scores alongside an increase in omega-3–derived eicosanoids, suggesting a distinct therapeutic effect attributable to high daily doses of EPA and DHA. Furthermore, omega-3–enriched parenteral nutrition is recognized as a key component of postoperative care and the management of critically ill patients, as emphasized in current guidelines on intravenous lipid emulsions [149]. Although the meta-analysis assessing fish oil supplementation in psoriasis indicated no statistically significant improvement in PASI scores compared to controls (MD −0.28; 95% CI −1.74 to 1.19; I2 = 57%), individual studies within the analysis reported trends toward improvement in body surface area, as well as reductions in erythema, scaling, and induration, particularly when fish oil was combined with adjunctive therapies [150]. Morin et al. demonstrated in in vitro models of psoriatic and healthy skin that supplementation with DHA or EPA—exerts notable anti-inflammatory and homeostatic effects. DHA reduced abnormal keratinocyte differentiation, lowered pro-inflammatory mediators (PGE2, 12-HETE, TNF-α), and rebalanced PPAR expression, thereby attenuating psoriatic characteristics [55]. EPA supplementation enriched epidermal omega-3 lipid content, increased anti-inflammatory metabolites (PGE3, 12-HEPE, EPEA), and decreased omega-6–derived products, restoring lipid and inflammatory equilibrium [58]. Moreover, DHA supplementation may also regulate epidermal keratinization processes [53]. In approximately 75% of psoriasis cases, a deletion of two late cornified envelope genes (LCE3B–C) is observed [151]. DHA and other omega-3 FAs have been shown to act as potent modulators of epidermal inflammation and differentiation in psoriasis. An open question remains regarding the precise pathways through which omega-3 FAs exert their beneficial effects in alleviating psoriasis. It has been postulated that these mechanisms involve competition as substrates for COX, increased production of SPMs, and modulation of the FFA4 receptor [54,57]. Two studies investigating a synthetic FFA4 agonist yielded conflicting results. A study led by Wannick et al. [54] reported no improvement in a murine model of psoriasis. In contrast, Son et al. observed both clinical improvements and reductions in pro-inflammatory mediators, confirming that the effects were mediated via the FFA4 receptor [57]. Notably, the two studies differed in the route of administration (oral versus parenteral, respectively), which may account for the observed discrepancies.
4.4.3. Evidence for SPMs in Psoriasis
Although the clinical effects of omega-3 supplementation may result from multiple mechanisms, experimental evidence suggests that enhanced SPMs biosynthesis and modulation of the IL-23/IL-17 axis play a key role. The first direct evidence supporting this theory dates back to 2011, when a research team demonstrated that lipoxin A4, in vitro, inhibits the expression of IL-6 and TNF-α in both keratinocytes and fibroblasts [45]. In line with these findings, treatment with a synthetic LXA4 agonist markedly reduced psoriatic inflammation in a murine model [46]. Similarly, Xu et al. demonstrated that pretreatment with RvD1 attenuated imiquimod (IMQ)-induced psoriasiform dermatitis by activating ALX/FPR2, leading to the suppression of the IL-23/IL-17 inflammatory axis [47]. A key downstream pathway implicated in post-receptor signaling involves high-mobility group box protein 1 (HMGB1), a pro-inflammatory mediator that amplifies the IL-23/IL-17A pathway, promotes keratinocyte activation, and facilitates the recruitment of immune cells to psoriatic lesions [152]. Elevated HMGB1 levels have been correlated with disease severity and the persistence of inflammatory responses in psoriasis [152].
Several other SPMs, including RvE1 and PD1, have also been identified as potent modulators of psoriatic inflammation [48,49]. Their administration reduces epidermal scaling, plaque thickness, and erythema, reflecting restoration of epidermal homeostasis. In addition, these mediators downregulate key cytokines involved in psoriasis pathogenesis. In preclinical models, SPMs have been shown to downregulate IL-17 and TNF-α expression, suppress the Th17 axis, reduce immune cell infiltration, and mitigate psoriasiform skin inflammation, highlighting their potential as pro-resolving therapeutic agents [47,48]. In murine models, omega-3 FA supplementation increased cutaneous levels of pro-resolving mediators, including RvD5, protectin DX, and MaR2, while EPA reduced pro-inflammatory PGE2 and TXB2 [50]. These findings indicate that omega-3 supplementation can simultaneously enhance resolution pathways and suppress pro-inflammatory eicosanoids. RvD1 and RvD5 reduce keratinocyte-driven inflammation by downregulating IL-24 and S100A12, suggesting their potential to attenuate psoriatic plaque formation and limit immune cell recruitment in affected skin [52].
Human data on SPMs in psoriasis remain limited and derive from only two studies [51,52]. These investigations compared lipid mediator profiles in the serum and skin biopsies of patients with psoriasis versus healthy controls, and additionally assessed differences between lesional and non-lesional skin within affected individuals. Within psoriatic lesions, an increase in DHA–derived metabolites (14-HDHA and 17-HDHA) was observed, suggesting partial activation of DHA-associated resolution pathways [52]. Conversely, metabolites originating from EPA, such as 14,15-epoxyeicosatetraenoic acid (14,15-EpETE) and 17,18-epoxyeicosatetraenoic acid (17,18-EpETE), were scarcely detectable or absent [51]. This pattern suggests a disruption or insufficiency in the EPA-derived lipid mediator pathway, leading to an incomplete activation of resolution-phase processes. Several omega-3 and omega-6 metabolites found in the skin were also detected in the bloodstream, although their differences were less marked. Higher serum hydroxyeicosatetraenoic acid (HETE) levels, an oxylipin derived from AA, in healthy individuals and comparable RvD2 detection across groups suggest that lipid mediator dysregulation in psoriasis is largely confined to the skin, making serum not representative for local inflammatory activity [51]. Clinically, localized disruption of lipid mediator homeostasis may sustain chronic skin inflammation despite modest systemic involvement. Thus, circulating biomarkers may have limited diagnostic value, while interventions that restore lipid balance—such as omega-3 supplementation, LOX/COX modulation, or correction of lipid oxidation and bile acid metabolism—could support resolution of psoriatic inflammation.
In summary, current evidence underscores the pivotal yet underexplored role of specialized SPMs and omega-3–derived lipids in psoriasis. Alterations in cutaneous lipid mediator networks—characterized by a relative deficiency of omega-3–derived pro-resolving metabolites and dominance of omega-6–driven inflammation—appear to impair resolution pathways and perpetuate chronic skin inflammation. These findings highlight the therapeutic potential of targeting lipid metabolism and enhancing SPMs biosynthesis as complementary strategies for restoring immune and epidermal homeostasis in psoriasis.
4.5. Hidradenitis Suppurativa
HS is a chronic, relapsing inflammatory skin disease characterized by a pathogenic triad of aberrant immune activation, dysregulated metabolic signaling, and impaired epithelial differentiation [153]. It predominantly affects intertriginous areas, including the axillae, groin, inframammary, and perianal regions, where it manifests as recurrent painful nodules, abscesses, and draining sinus tracts [154]. The disease follows a debilitating course and profoundly impacts multiple aspects of patients’ lives, including occupational functioning, social interactions, and sexual health, often resulting in significant psychosocial distress and social isolation [155]. HS is frequently associated with a range of systemic comorbidities, most notably components of metabolic syndrome. Estimates suggest that up to half of all patients with HS meet the diagnostic criteria for metabolic syndrome, including obesity, hypertension, dyslipidemia, and insulin resistance [156]. The chronic inflammatory state contributes to a markedly increased overall health burden. Consequently, individuals with HS experience a substantially reduced life expectancy, with some studies reporting a decrease of approximately 15 years compared to the general population [157].
This elevated morbidity and mortality underscore the systemic nature of the disease. HS is characterized by a dominant Th1/Th17 immune response, with lesional skin exhibiting elevated levels of pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-17, and IL-23 [154]. Existing evidence indicates that HS is characterized by both systemic lipid dysregulation and a localized imbalance of cutaneous lipid mediators. Lesional skin exhibits impaired regulation of sphingolipid-metabolizing enzymes, with a shift toward catabolic pathways [157]. Recent lipidomic analyses in HS have revealed systemic alterations in lipid metabolism, particularly dysregulation of sphingolipid pathways, and elevated levels of pro-inflammatory oxylipins—such as HETEs and DHETs—correlating with disease activity [158]. Although systemic changes were less pronounced than those observed in lesional skin [159], the study’s methodological design ensured that the detected changes reflected a disease-specific lipid imbalance independent of metabolic comorbidities.
To date, direct evidence concerning SPMs in HS is lacking; therefore, this section aims to summarize the available data on pro-inflammatory lipid mediators and identify existing gaps in the current literature. Lipidomic profiling of lesional HS skin revealed a distinct pro-inflammatory shift, characterized by elevated levels of 5-LOX–derived metabolites from AA—notably 5-HETE, 5-oxo-eicosatetraenoic acid (5-oxo-ETE), and leukotriene B4 (LTB4) —accompanied by reduced concentrations of anti-inflammatory products generated via 12-LOX and 15-LOX pathways from EPA and DHA [133]. Although the study did not directly measure SPMs, the observed reduction in 15-hydroxyeicosapentaenoic acid (15-HEPE)—a key precursor of E-series resolvins—indirectly suggests a diminished capacity for SPMs biosynthesis. This deficiency may contribute to the chronic, non-resolving Th1/Th17-driven inflammatory phenotype characteristic of HS, while highlighting the potential underrepresentation of pro-resolving pathways in the lesional lipidome. Taken together, these findings underscore a clear pro-inflammatory lipid signature in HS but also point to several important gaps in knowledge that require further investigation. First, the detailed composition of FAs in both lesional and circulating compartments of HS patients—particularly the balance between omega-3 and omega-6 species—remains poorly characterized. Second, the specific contributions of pro-resolving lipid mediators to HS pathophysiology have been largely unexplored, with the majority of existing data focusing on pro-inflammatory eicosanoids. Third, it remains unclear whether lipid dysregulation acts as a primary driver of HS pathogenesis or arises secondarily as a consequence of chronic inflammation. Finally, therapeutic strategies targeting lipid pathways—such as dietary modulation of FAs or pharmacologic manipulation of lipid mediators—are urgently needed, given that outcomes achieved with currently available treatments, which primarily focus on the inhibition of pro-inflammatory cytokines, remain largely unsatisfactory.
4.6. Acne Vulgaris
Acne vulgaris is a common chronic dermatological condition involving the pilosebaceous unit. It is one of the most prevalent diseases worldwide, affecting approximately 9.4% of the global population [160], and its incidence appears to be increasing [74]. The condition may manifest with non-inflammatory lesions (open and closed comedones) as well as inflammatory lesions (papules, pustules, and nodules) [161]. Although acne typically begins during adolescence and predominantly affects young males, it may also develop in adults, among whom it is more frequently observed in women. The pathogenesis of acne involves increased follicular keratinization, excess production of sebum, inflammation, and colonization of the hair follicles by Cutibacterium acnes [161]. Genetic and ethnic factors influence acne susceptibility; however, increasing incidence has been associated with the adoption of Western lifestyles, which are characterized by low intake of PUFAs and high consumption of saturated fats and refined carbohydrates [162]. Acne affects daily functioning, causing feelings of embarrassment, anxiety, and discomfort [163].
Initially, inflammation was described as occurring in the later stages of acne, accompanying clinical lesions such as papules and pustules. More recent studies, however, indicate that inflammation is also present in the early stages of acne development [77,164]. Moreover, evidence suggests that inflammation may precede hyperkeratinization of the pilosebaceous unit. This is supported by the observation of elevated levels of CD3+ and CD4+ T cells in the perifollicular and papillary dermis, as well as an increased number of macrophages in clinically unaffected skin in acne patients [165,166].
Scientific studies indicate possible lipid abnormalities in patients with acne. Sobhan et al. demonstrated significantly higher total cholesterol levels, particularly among male patients with acne [167]. Other lipid parameters (triglicerydes, LDL, and HDL) were higher in the acne group than in controls, but the differences were not statistically significant. Jiang et al. reported significantly elevated levels of total cholesterol, LDL, and lipoprotein A in acne patients compared to control groups, with male patients also showing higher triglyceride levels [168]. Research suggests that certain lipid components and their ratios—particularly the omega-6/omega-3 and PUFA/MUFA ratios—may have a causal influence on acne risk [137]. Gokdemir et al. found statistically higher serum triglyceride concentrations in patients with acne [169]. Although the existing data present inconsistent findings, they collectively highlight potential directions for future large-scale investigations.
The enzyme lipoprotein lipase (LPL) catalyzes the hydrolysis of triglycerides in plasma triglyceride-rich lipoproteins at the surface of capillary endothelial cells. Its expression has also been detected in skin appendages, implying that sebaceous glands possess the ability to sequester FAs, which may be associated with the pathogenesis of acne [73]. The angiopoietin-like proteins (ANGPTLs) 3 and 4 are the main regulators of plasma lipid metabolism due to their inhibitory effect on LPL. Secretory PLA2, hydrolyzes phospholipids, generating free FAs and lysophospholipids, which exacerbate the inflammation [73]. Aslan et al. demonstrated increased activity of sPLA2 and elevated AA/EPA and dihomylo-γ-gamma-linoleic acid/eicosapentaenoic acid (DGLA/EPA) ratios in patients with acne. Significantly higher activity of LPL was also observed in the same cohort [73]. The activities of both enzymes in sebaceous glands generate free FAs that can fuel inflammation leading to acne pathogenesis.
Recent studies have begun to elucidate the relationship between lipids and inflammation in acne, with particular emphasis on PUFAs [73,74,75,77,160,168,169]. Among these studies, omega-3 supplementation was associated with an improvement in acne lesions [71,137,165,167], and with a beneficial effect on gut microbial diversity [76]. However, current evidence regarding PUFA-enriched diets remains limited due to small sample sizes, heterogeneous interventions, and inconsistent outcome measures. Moreover, during systemic acne therapy with isotretinoin, omega-3 FAs were shown to reduce some of the drug’s adverse effects [74]. In contrast to omega-3, the role of omega-6 FAs in acne remains unclear. γ -linoleic acid (GLA) appears to improve acne lesions [72], whereas Zhang et al. demonstrated that DGLA may exacerbate acne [77]. Additionally, AA and EPA were identified as protective factors against the development of inflammation in acne [77]. In acne vulgaris patients higher levels of AA/EPA and DGLA/EPA ratios were observed [73]. These findings suggest that a higher dietary intake of omega-3 FAs, combined with reduced consumption of saturated fats, may exert a beneficial therapeutic effect in the management of acne. Furthermore, Zhang et al. identified several SNPs within the fatty acid desaturase 1 (FADS1) and fatty acid desaturase 2 (FADS2) genes. These variants may affect the enzymatic activity of FADS1 and FADS2 in PUFA metabolism, thereby contributing to the worsening of acne symptoms [77]. Personalized approaches based on lipid and genomic profiling could therefore help optimize therapeutic outcomes in acne patients.
Acne vulgaris is associated with a mixed but predominantly Th1/Th17-type immune response, characterized by elevated levels of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, IL-17 and TNF-α, which contribute to follicular inflammation, neutrophil infiltration and lesion formation [170,171]. Emerging evidence suggests that SPMs can limit pro-inflammatory cytokine production and leukocyte infiltration, thereby promoting resolution of inflammation and offering potential therapeutic benefits in acne. So far, no direct link has been established between SPMs and acne development. However, the involvement of inflammatory processes in the early stages of acne formation and comedogenesis, together with the beneficial effects of omega-3 FAs on the course of the disease, suggests that inadequate resolution of inflammation and disturbances in lipid mediator homeostasis may contribute to the pathogenesis of acne vulgaris. While SPMs represent a promising new direction for acne research, the beneficial effects of omega-3 FAs cannot be explained solely by their conversion to SPMs. Omega-3 FAs exert multifaceted biological actions among which the bactericidal activity of long chain PUFAs against Cutibacterium acnes and Staphylococcus aureus appears particularly relevant to acne pathogenesis [39]. Moreover, omega-3 FAs provide alternative substrates for LPL and sPLA2, potentially reducing the synthesis of pro-inflammatory mediators. Thus, understanding how SPMs and PUFA-derived lipid mediators contribute to the regulation of inflammation and microbial balance in acne may open new therapeutic perspectives.
4.7. Atopic Dermatitis
Similar to psoriasis, AD is characterized by an imbalance between pro- and anti-inflammatory lipids, prompting investigation into the role of omega-3 FAs and SPMs in this condition. AD constitutes a major global dermatological health burden, affecting approximately 10–20% of children and up to 3% of adults [172]. Multifactorial pathogenesis of AD encompasses genetic predisposition, epidermal barrier dysfunction, immune dysregulation, and environmental determinants [18,101]. Of particular note, the prevalence of AD has shown a progressive increase over recent decades, a trend partly attributed to changes in dietary habits, particularly the shift toward higher consumption of omega-6 PUFAs and the resulting imbalance in the omega-6 to omega-3 ratio [173]. Growing evidence indicates that disruption of the omega-6 to omega-3 ratio contributes to dysregulated eicosanoid signaling and persistent inflammation [174].Immunologically, acute AD is primarily mediated by a Th2-dominant response, with heightened expression of IL-4, IL-5, IL-13, IL-31, and occasionally IL-22, while chronic or treatment-resistant lesions frequently involve additional activation of Th1, Th17, and Th22 pathways [175].
At the molecular level, omega-3–derived lipid mediators exert pleiotropic immunomodulatory and barrier-stabilizing effects on the cutaneous microenvironment characteristic of AD [78,80,81,82]. EPA and DHA compete with AA for COX and LOX pathways, thereby reducing the generation of pro-inflammatory eicosanoids such as PGE2 and LTB4 [81,83]. In parallel, the conversion of EPA and DHA into specialized pro-resolving lipid mediators actively terminates inflammation through the downregulation of Th2- and Th17-driven cytokines (IL-4, IL-5, IL-13, IL-17A) and the suppression of IgE synthesis [80,82]. These mediators also enhance regulatory T-cell (Treg) activity, promote macrophage M2 polarization, and restore epidermal barrier integrity by normalizing ceramide synthesis and reducing TEWL [44,80]. Given the dominant Th2 cytokine milieu in acute AD, which expands to include Th17 and Th22 responses in chronic stages, SPM-mediated downregulation of IL-4, IL-13, and other inflammatory mediators offers a promising mechanism to rebalance immune responses, support barrier repair, and potentially reduce pruritus and allergen sensitivity. Indeed, impaired generation of SPMs has been proposed as a contributing factor to the chronic, non-resolving inflammation in AD, and restoration of pro-resolving lipid mediator pathways is increasingly viewed as a potential novel therapeutic strategy [176].
Dietary modulation of PUFA intake and direct SPMs administration have been explored as therapeutic approaches for AD [78,79,81,82,83,89,90,92,93,96,97,99,101]. The following studies, summarized in Table 4, encompass both clinical and preclinical investigations exploring the influence of omega-3/omega-6 FAs and SPMs on the onset and severity of AD. These studies evaluate diverse interventions—including maternal supplementation during pregnancy, direct oral intake of EPA/DHA, topical formulations, and experimental administration of SPMs analogues—in both human cohorts and animal models. Experimental studies consistently demonstrate that EPA- and DHA-derived mediators attenuate Th2/Th17 inflammation, reduce IgE and histamine levels, and restore epidermal lipid balance, thereby improving barrier function [78,79,80,81,82,84]. These effects are further supported by data showing enhanced Treg activity and suppression of pro-inflammatory cytokines following SPMs or omega-3 administration [80,96].
In contrast, clinical findings are more heterogeneous: while several randomized controlled trials and maternal supplementation studies report reduced IgE-associated eczema [95], decreased allergen sensitization, or milder disease severity [93], others find no significant preventive or therapeutic effects [89,90,96,99]. Recent trials further substantiate both the potential and the limitations of omega-3 interventions. Supplementation with DHA/EPA in adults and children with AD has been shown to significantly reduce SCORAD scores and improve patient-reported outcomes [94,101], and maternal omega-3 intake during pregnancy was associated with a lower incidence of IgE-mediated eczema in infants [95]. In the context of SPMs and omega-3/omega-6 FAs in AD, there is emerging evidence that maternal DHA intake may modify the increased risk of AD associated with prenatal arsenic exposure [100]. However, other well-controlled studies demonstrated no reduction in eczema risk despite clear biochemical evidence of increased maternal and infant DHA/EPA levels and dampened cytokine responses [96,99]. Such discrepancies may be attributed to heterogeneity in population risk profiles, baseline dietary patterns, genetic factors, and timing or dosage of supplementation. Recent meta-analytic evidence indicates that although maternal omega-3 PUFAs supplementation during pregnancy does not significantly reduce the overall incidence of eczema in offspring, it may confer a potential subgroup benefit for IgE-associated eczema in children under three years of age, highlighting age-dependent and immunophenotype-specific effects of prenatal omega-3 exposure [177]. Overall, while omega-3 FAs exhibit immunomodulatory and barrier-stabilizing properties, the inconsistency of clinical outcomes precludes universal recommendations and highlights the multifactorial nature of AD pathophysiology.
Consequently, attention has increasingly shifted toward SPMs, which exert potent anti-inflammatory and pro-resolving actions at nanomolar concentrations [124]. Their ability to actively terminate inflammation and promote tissue homeostasis has drawn researchers’ attention to the development of stable analogues or receptor agonists for clinical application. To date, the only human study in AD utilizing an SPMs-based approach evaluated a topical 15(R/S)-methyl-lipoxin A4 cream in infants with acute facial eczema, which significantly improved erythema, pruritus, and lesion severity within days [98]. Moreover, the cream demonstrated comparable efficacy to medium-potency corticosteroids without adverse effects; however, the relapse rate at 40 days was higher than in the control group treated with mometasone [98]. These findings suggest that targeting the SPM pathway may represent a promising, mechanism-driven therapeutic strategy distinct from conventional anti-inflammatory treatments.
4.8. Integrated Summary of Findings and Overall Limitations
Across psoriasis, AD, acne, and HS, the findings of this systematic review demonstrate that disturbances in lipid mediator networks—particularly imbalances between omega-3– and omega-6–derived metabolites—are consistently associated with aggravated inflammation, impaired barrier function, and dysregulated immune responses. Hidradenitis suppurativa, psoriasis, and acne vulgaris are predominantly Th1/Th17-driven, with elevated IL-17A, IL-17F, IL-23, TNF-α, and IFN-γ promoting keratinocyte activation, neutrophil recruitment, and chronic inflammation, whereas atopic dermatitis is primarily Th2-mediated, with IL-4, IL-5, IL-13, and IL-31 driving IgE production, barrier dysfunction, and allergic sensitization. SPMs modulate immune responses in a context-dependent manner, targeting the dominant T-helper cell profile: suppressing IFN-γ and TNF-α in Th1-driven diseases, downregulating IL-4, IL-5, and IL-13 in Th2-mediated disorders, and attenuating IL-17/IL-23 signaling and neutrophil-driven inflammation in Th17-skewed conditions. Across all contexts, SPMs enhance Treg activity and promote macrophage M2 polarization, providing a conserved mechanism for inflammation resolution and tissue repair. Human data remain limited but broadly align with experimental findings, suggesting that insufficient SPMs biosynthesis or precursor availability may contribute to chronic, non-resolving inflammation. Interventional studies involving omega-3 supplementation show variable but generally favorable outcomes in psoriasis, acne, and AD, particularly regarding patient-reported symptoms. Evidence in HS is minimal and indirect. Taken together, the evidence suggests that lipid mediators derived from PUFAs act as central regulators of immune resolution in the skin.
This body of evidence has notable limitations, including the scarcity of human studies, small cohorts, and heterogeneous interventions. Many trials depend on non-standardized or subjective outcomes, and dietary studies may be influenced by confounding factors, including lifestyle and genetic susceptibility. Moreover, mechanistic in vitro and animal data may not adequately reflect human physiology, reducing translational relevance. The reliance on mechanistic and animal studies, together with the probable underrepresentation of studies reporting null or negative outcomes, limits confidence in the estimated therapeutic benefits of omega-3 fatty acids and SPMs in humans.
This review also has methodological limitations. Only one database (MEDLINE/PubMed) was searched, which may have led to missed studies published elsewhere. A major limitation of this review is the lack of a formal risk-of-bias assessment. This was due to the substantial heterogeneity and mechanistic nature of the included evidence, which comprised in vitro studies, animal models, and exploratory human research—study types for which no unified risk-assessment framework exists. Additionally, highly variable methodologies, small sample sizes, and inconsistent outcome reporting across studies prevented meta-analysis, assessment of reporting bias, and formal evaluation of certainty of evidence. Moreover, considerable variability in analytical techniques for quantifying lipid mediators—including differences in sample preparation, detection platforms, and quantification methods—further limits comparability across studies and introduces potential measurement inconsistency. Additionally, publication bias could not be evaluated, and certainty of evidence was not assessed due to the nature of the included data.
Clinically, omega-3 supplementation may offer complementary benefits in inflammatory skin diseases, although current evidence is insufficient for formal recommendations. SPM-based therapies, particularly stable analogues and receptor agonists, represent a promising yet still emerging therapeutic direction. Future research should focus on well-designed clinical trials with standardized clinical and biochemical endpoints, comprehensive lipidomic profiling, and mechanistic work on SPM analogues and agonists, as these agents offer the most realistic route toward therapeutic translation.
5. Conclusions
Dysregulated lipid metabolism—particularly imbalances in omega-3 and omega-6–derived mediators—plays a central role in the pathogenesis of psoriasis, HS, acne vulgaris and AD. SPMs act at the interface of lipid metabolism, immune regulation, and tissue repair, facilitating the active resolution of cutaneous inflammation. Accordingly, omega-3 FAs and their downstream SPMs represent promising adjunctive therapies capable of restoring inflammatory balance and promoting tissue homeostasis. While mechanistic and early clinical data on SPMs are compelling, further research is needed to comprehensively characterize SPMs profiles in inflammatory skin disorders. Additional studies are also required to evaluate the therapeutic potential of SPM analogues and receptor agonists, particularly given their superior stability and receptor specificity compared with endogenous mediators. The limited available human data suggest that deficiencies in omega-3–derived pro-resolving mediators, together with a shift toward omega-6–dominant inflammatory profiles, may contribute to disease chronicity and severity. This imbalance highlights the relevance of targeting lipid mediator pathways as a complementary strategy to conventional anti-inflammatory therapies. To sum up, omega-3 FAs and SPMs represent promising adjuncts for managing several inflammatory skin conditions through their capacity to rebalance inflammatory pathways and promote resolution pathways.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/antiox15010009/s1, The full PubMed search strategy, including MeSH terms, keywords, and Boolean operators, is provided in Supplementary File S1. Ref [178] was cited in the Supplementary Materials.
Author Contributions
Conceptualization, A.B.-B. and O.J.-Z.; methodology, A.B.-B. and H.M.; software, N/A; validation, N/A; formal analysis, N/A; investigation, N/A; resources, A.B.-B. and O.J.-Z.; data curation, A.B.-B. and O.J.-Z.; writing—original draft preparation, A.B.-B. and O.J.-Z.; writing—review and editing, H.M. and I.F.; visualization, A.B.-B. and O.J.-Z.; supervision, I.F.; project administration, H.M.; funding acquisition, N/A. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by the Publication Fund of the Medical University of Bialystok.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
All data analyzed in this systematic review are publicly available from the cited publications. The full study protocol and search strategy are archived and accessible at [https://doi.org/10.17605/OSF.IO/FV9PR]. No new primary data were generated.
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
The following abbreviations are used in this manuscript:
| 14,15-EpETE/17,18-EpETE | 14,15-Epoxyeicosatetraenoic Acid/17,18-Epoxyeicosatetraenoic Acid |
| 14-HDHA/17-HDHA | 14-Hydroxydocosahexaenoic Acid/17-Hydroxydocosahexaenoic Acid |
| 5-HETE/12-HETE/12-HEPE/15-HEPE | 5-Hydroxyeicosatetraenoic Acid/12-Hydroxyeicosatetraenoic Acid/12-Hydroxyeicosapentaenoic Acid/15-Hydroxyeicosapentaenoic Acid |
| 5-oxo-ETE | 5-Oxo-Eicosatetraenoic Acid |
| AA | Arachidonic Acid |
| AC | Acne Comedonica |
| AD/AD-lika | Atopic dermatitis/Atopic dermatitis like |
| ALA | α-Linolenic Acid |
| ALX/FPR2 | Lipoxin A4 Receptor/Formyl Peptide Receptor 2 |
| AP | Acne Papulopustulosa |
| AT/ATL | Aspirin triggered/Aspirin triggered lipoxin |
| BALB/c | Bagg Albino Laboratory-bred Mouse Strain c |
| BLT1 | Leukotriene B4 Receptor 1 |
| BSA | Body Surface Area |
| CBMC | Cord blood mononuclear cell |
| CCL2 | C-C motif chemokine ligand 2 |
| CD80/86 | Co-stimulatory molecules expressed on antigen-presenting cells |
| CI | Confidence Interval |
| COX/COX-2/acetyl-COX-2 | Cyclooxygenase/Cyclooxygenase-2/aspirin-acetylated cyclooxygenase-2 |
| CRP | C-Reactive Protein |
| CTLA-4 | Cytotoxic T-lymphocyte-associated protein 4 |
| CYP-450 | Cytochrome P450 Enzyme System |
| CXCL10 | C-X-C motif chemokine ligand 10 |
| DGLA | Dihomo-γ-Linolenic Acid |
| DHA | Docosahexaenoic Acid |
| DHA-M2 | Docosahexaenoic acid–induced M2 macrophages |
| DHET | Dihydroxyeicosatrienoic Acid |
| DLQI | Dermatology Life Quality Index |
| DNCB | 2,4-dinitrochlorobenzene |
| DNFB | 2,4-dinitrofluorobenzene |
| DPA | Docosapentaenoic Acid |
| EASI | Eczema Area and Severity Index |
| ECM | Extracellular Matrix |
| ELOVL | Elongation of Very Long Chain Fatty Acids Protein (family) |
| EPA/EPA-E | Eicosapentaenoic Acid/eicosapentaenoic acid ethyl ester |
| ERK1/2 | Extracellular Signal–Regulated Kinases 1/2 |
| FAs | Fatty acids |
| FABP | Fatty Acid–Binding Protein |
| FADS2 | Fatty acid desaturase 2 |
| FDLQI | Family Dermatology Life Quality Index |
| FFA4R/GPR120 | Free Fatty Acid Receptor 4 |
| FK506 | Tacrolimus |
| FMT | Fecal Microbiota Transplantation |
| GLA | γ-linolenic acid |
| GPCR | G Protein–Coupled Receptor |
| HDL | High-density lipoprotein |
| HETE | Hydroxyeicosatetraenoic Acid |
| HEPE | Hydroxy-eicosapentaenoic Acid |
| HMGB | High-Mobility Group Box protein |
| HpEPE | Hydroperoxy-eicosapentaenoic Acid |
| HpETE | Hydroxyperoxy-eicosatetraenoic Acid |
| HR-AD | Hairless atopic dermatitis |
| HRO | Herring Roe Oil |
| HS | Hidradenitis Suppurativa |
| IgE | Immunoglobulin E |
| IL | Interleukin |
| IRI/I–R | Ischemia–Reperfusion Injury |
| ISAAC | International Study of Asthma and Allergies in Childhood |
| IV | Intravenous |
| IMQ | Imiquimod |
| KO | Knockout |
| LCE3B–C | Late Cornified Envelope Genes 3B and 3C |
| LC-PUFA | Long-chain polyunsaturated fatty acid |
| LN | Lymph node |
| LOX/5-LOX/12-LOX/15-LOX | Lipoxygenase/5- Lipoxygenase/12- Lipoxygenase/15- Lipoxygenase |
| LPL | Lipoprotein Lipase |
| LPS | Lipopolysaccharide |
| LT/LTA4/5/LTE4/5 | Leukotriene A4/5—E4/5 |
| LXA4/LXA5 | Lipoxin A4/A5 |
| M2 | Alternatively Activated Macrophage Phenotype |
| MAPK | Mitogen-Activated Protein Kinase |
| MaR1/MaR2 | Maresin-1/Maresin 2 |
| MCT | Medium-chain triglyceride |
| MCTR | Maresin Conjugates in Tissue Regeneration |
| MD | Mean difference |
| MR | Mendelian Randomization |
| MUFA | Monounsaturated fatty acid |
| NF-κB | Nuclear Factor kappa-light-chain-enhancer of activated B cells |
| NHDF | Normal Human Dermal Fibroblasts |
| NHEK | Normal Human Epidermal Keratinocytes |
| NK | Natural Killer Cells |
| NRF2 | Nuclear Factor Erythroid 2–Related Factor 2 |
| NSAID | Non-Steroidal Anti-Inflammatory Drug |
| PASI | Psoriasis Area and Severity Index |
| PAF | Platelet-activating factor |
| PBMC | peripheral blood mononuclear cell |
| PG/PGE2/PGE3/PGH2/PGG2 | Prostaglandin/E2/E3/H2/G2 |
| PGI2 | Prostacyclin |
| PSO | Psoriasis |
| PUFA | Polyunsaturated Fatty Acid |
| PD1 | Protectin D1 |
| PDX | Protectin DX |
| PLA2/PLA2G4E/sPLA2 | Phospholipase A2/Phospholipase A2 Group IVE/Secretory Phospholipase A2 |
| PPAR | Peroxisome Proliferator–Activated Receptor |
| PRS | Polygenic risk score |
| RCT | Randomized Controlled Trial |
| QoL | Quality of life |
| RvD1-RvD6 | Resolvin D1-D6 |
| RvE/RvE1–RvE4 | Resolvin E-series/E1/E2/E3/E4 |
| S100A12 | S100 Calcium-Binding Protein A12 |
| SCORAD | SCORing Atopic Dermatitis |
| SFA | Saturated fatty acid |
| SNP | Single-nucleotide polymorphism |
| SPMs | Specialized Pro-Resolving Mediators |
| SSS | Symptom Severity Score |
| STAT1 | Signal Transducer and Activator of Transcription 1 |
| TCM | Central Memory T cells |
| TCS | Topical corticosteroid |
| TEWL | Transepidermal Water Loss |
| TG | Trigliceride |
| TGF-β | Transforming growth factor-β |
| Th/Th2/Th17 | Helper T Cell/Type 2 Helper T Cell/Type 17 Helper T Cell |
| TN | Naïve T cells |
| TNF-α | Tumor Necrosis Factor α |
| Treg | Regulatory T cell |
| TSLP | Thymic stromal lymphopoietin |
| TXA2/TXB2 | Thromboxane A2/B2 |
| UFA | Unsaturated Fatty Acid |
| UV | Ultraviolet |
| VDR | Vitamin D Receptor |
| WT | Wild-Type |
| ω-3 | Omega-3 Fatty Acids |
| ω-6 | Omega-6 Fatty Acids |
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