Hidradenitis suppurativa is a chronic inflammatory dermatosis characterized by painful, recurrent nodules, abscesses, and draining tunnels, known as sinus tracts, most commonly in the axillae, groin, and perineal regions. It arises from inflammation centered on the hair follicles in areas rich in apocrine glands, and it follows a relapsing-remitting course that can span decades. The disease is far from rare, affecting an estimated one percent or more of the population, yet it remains underdiagnosed and frequently mistaken for simple boils or infections. Beyond its physical toll, the condition is notorious for its impact on quality of life: lesions in sensitive body regions, malodorous drainage, scarring, and unpredictable flares contribute to social isolation, sexual dysfunction, and profound psychological distress. For years, clinicians have observed that patients with hidradenitis suppurativa suffer from depression, anxiety, and suicidality at rates that dwarf those seen in the general population and in many other chronic dermatologic diseases.

What distinguishes the new research letter by Rehman Basharat of the Renaissance School of Medicine at Stony Brook University and Javed Iqbal of Stony Brook’s Department of Neurobiology and Behavior is its deliberate reversal of the conventional causal arrow. Most prior investigations, including a widely cited 2020 systematic review and meta-analysis published in the Journal of the American Academy of Dermatology, examined depression, anxiety, and suicidality as outcomes of living with hidradenitis suppurativa. That meta-analysis confirmed strikingly elevated odds of psychiatric comorbidity among patients, cementing the skin-to-mind pathway in the literature. The Stony Brook team instead asked whether depression might come first—whether a diagnosis of depression increases the subsequent likelihood of developing hidradenitis suppurativa. By structuring the analysis as a retrospective cohort using real-world data, the investigators could track individuals over time and examine the temporal sequence between the psychiatric and dermatologic conditions, an approach that cross-sectional surveys simply cannot support.

The biologic plausibility of such a reverse pathway rests on a rapidly growing understanding of the immunology of depression itself. Far from being a purely neurochemical disorder, major depression is increasingly recognized to carry a systemic inflammatory signature. Landmark work, including the influential 2016 review by Andrew Miller and Charles Raison in Nature Reviews Immunology, has documented elevated circulating pro-inflammatory cytokines, increased acute-phase reactants, and altered immune cell activity in subsets of depressed patients. Cytokines such as interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha can cross into or signal within the central nervous system, but their effects are by no means confined to the brain. These same molecular messengers are central drivers of cutaneous inflammation. In hidradenitis suppurativa specifically, the pathophysiology is understood to involve follicular occlusion followed by an intense, dysregulated immune response dominated by innate inflammatory pathways and a characteristic overexpression of tumor necrosis factor alpha, interleukin-17, and interleukin-23 in lesional skin. A 2024 narrative review in Skin Appendage Disorders meticulously mapped this cytokine-mediated molecular architecture of the disease, highlighting how TNF-alpha in particular orchestrates the chronic inflammatory cascade that destroys follicular structures and produces the fistulating lesions that define advanced disease.

The convergence of these two inflammatory profiles is what gives the new hypothesis its scientific traction. Depression is associated with elevated TNF-alpha and other cytokines; hidradenitis suppurativa is driven by the same mediators. If a state of chronic, low-grade systemic inflammation induced or maintained by depression were to lower the threshold for follicular inflammation, impair wound healing, or dysregulate the innate immune responses of the skin, then depressed individuals could plausibly face a heightened risk of developing manifest hidradenitis suppurativa. Behavioral and physiological factors common to depression may compound this immunologic pathway: sleep disruption, physical inactivity, smoking, obesity, poor diet, and altered hypothalamic-pituitary-adrenal axis activity are all more prevalent in depression and all have documented links to inflammatory skin disease severity. Cortisol dysregulation, in particular, is known to impair epidermal barrier function and dermal immune surveillance, mechanisms that have been studied extensively in the psychodermatology literature.

The Stony Brook authors are explicit that their work builds on earlier speculation in the field. A 2024 commentary in the journal Cutis raised exactly this possibility, arguing that depression could function as a potential contributing factor in hidradenitis suppurativa and highlighting racial gaps in how the association manifests, given the disease’s disproportionate burden on Black patients and the documented disparities in diagnosis and treatment access. A 2023 literature review in the journal Life catalogued the range of psychiatric disorders associated with hidradenitis suppurativa and explored their potential pathogenesis, concluding that the relationship is almost certainly bidirectional and biologically embedded rather than a simple byproduct of living with visible, painful lesions. By bringing retrospective cohort methodology and real-world data to bear, the new research letter provides an empirical test of what had been largely a hypothesis grounded in mechanistic plausibility and clinical observation.

The real-world data approach deserves particular emphasis, because it addresses a persistent weakness of the hidradenitis suppurativa literature. Randomized trials in the field, including those that established biologics such as TNF-alpha and IL-17 inhibitors as mainstay therapies, enroll selected patients under controlled conditions, and their findings do not always translate cleanly to the heterogeneous populations seen in routine practice. Recent real-world studies, such as 2025 evaluations of biologic therapy effectiveness published in the Australasian Journal of Dermatology, have demonstrated both the value and the limitations of translating trial results into everyday clinical care, including nuances in lipid profiles and treatment safety captured only in broader cohorts. A retrospective cohort built on real-world data captures patients of all disease severities, comorbidity profiles, and demographic backgrounds, offering a view of the depression-hidradenitis axis that reflects the population as it actually presents to clinicians rather than as it appears in protocol-driven trials.

For clinicians, the implications of a depression-to-hidradenitis risk pathway would be considerable. Dermatologists managing patients with early or suspected hidradenitis suppurativa routinely screen for psychiatric comorbidity, and European S1 guidelines for the disease’s treatment explicitly recommend attention to quality of life and psychological burden as part of comprehensive care. But if depression is also a risk factor, the screening logic inverts: psychiatrists and primary care physicians treating depressed patients, particularly those with inflammatory comorbidities, obesity, or smoking, might reasonably maintain a heightened index of suspicion for early follicular inflammation in intertriginous areas, enabling diagnosis before the disease progresses to painful scarring and sinus tract formation. Early intervention matters enormously in this disease, since treatments ranging from wound care and antibiotics to biologics and surgery are far more effective before irreversible structural damage occurs. The findings also raise provocative questions about whether effective depression treatment could modify hidradenitis risk, an intervention trial that no one has yet conducted but that the current study’s results would seem to justify.

The authors are careful to frame their work within the constraints of the retrospective design. Observational cohort data can establish temporal sequence and statistical association, but cannot by itself prove causation; unmeasured confounders, including shared genetic susceptibilities, medication effects, and healthcare utilization patterns, may partly explain the observed relationship. The research letter format likewise signals a concise, focused analysis intended to stimulate further work rather than to settle the question definitively. Both authors contributed to writing the manuscript, with Basharat preparing the figure and table, and both reviewed and approved the final text. The authors declare no competing interests, and the data supporting the findings are provided within the manuscript itself. Correspondence for the study is directed to Javed Iqbal in Stony Brook’s Department of Neurobiology and Behavior.

Nevertheless, the study lands at a moment when the broader concept of the mind-skin axis is gaining scientific respectability. Psychodermatology, once a niche corner of both dermatology and psychiatry, now commands growing attention as immunologic research reveals the molecular common ground between mental states and skin inflammation. The inflammatory hypothesis of depression has prompted trials of anti-inflammatory agents as antidepressant adjuncts; conversely, dermatologists increasingly recognize that calming systemic inflammation can lift mood. Hidradenitis suppurativa, with its uniquely severe psychiatric comorbidity burden and its cytokine biology so clearly intertwined with the inflammatory signature of depression, may prove to be one of the clearest natural laboratories for studying this bidirectional relationship. If future prospective studies confirm that depression accelerates or precipitates the disease, the Standard of care could expand to include collaborative, multidisciplinary management in which mental health treatment is viewed not only as supportive care but as a genuine component of dermatologic prevention. For the millions of patients who endure this condition in silence, often for years before diagnosis, the recognition that their psychological suffering and their skin disease are two faces of a single inflammatory biology represents both scientific progress and long-overdue clinical empathy.

Psoriasis, a common and debilitating autoimmune skin disease, arises from complex interactions between keratinocytes and immune cells. Classical models emphasize the pivotal functions of IL-17 cytokines secreted predominantly by Th17 cells in sustaining skin inflammation and hyperproliferation of keratinocytes. However, the exact molecular underpinnings integrating cellular metabolism, chromatin remodeling, and cytokine signaling within keratinocytes have remained largely unexplored until now. The current investigation leverages cutting-edge epigenomic and molecular biological methodologies to bridge this knowledge gap.

Central to the study is the identification of lactylation—a newly characterized post-translational modification of histones—as a key epigenetic mark modulating keratinocyte function. Histone lactylation, induced by high intracellular lactate levels typical in inflamed tissue microenvironments, was found to specifically enrich at the H4K12 residue within epidermal keratinocytes during psoriatic lesions. This modification appears to act as a metabolic sensor that translates shifts in cellular metabolism into durable changes in chromatin accessibility, thereby regulating gene expression programs relevant to inflammation.

Through the use of genetically engineered mice with keratinocyte-restricted modifications ablating or mimicking H4K12 lactylation, the researchers demonstrated that this modification is indispensable for robust psoriasis development. Mechanistically, H4K12la modifies chromatin landscapes at loci encoding a distinct subset of signaling molecules, diverging from canonical IL-17 pathways classically studied in immune cells. These keratinocytes exhibit an IL-17-dependent, yet transcriptionally unique, signaling cascade that amplifies local inflammation and epidermal hyperplasia, hallmarks of psoriatic skin.

Perhaps most strikingly, this research highlights a non-canonical signaling axis wherein keratinocytes themselves participate actively in immune crosstalk through this epigenetic reprogramming, rather than serving solely as passive targets of immune-mediated damage. The traditional view of psoriasis pathogenesis, heavily centered on immune cells such as Th17 subsets, is now complemented by an appreciation of keratinocytes as dynamic immune modulators governed by histone lactylation states.

Biochemically, lactate accumulation in dermal lesions arises from altered metabolic fluxes in the inflamed microenvironment, a characteristic shared across many autoimmune conditions. This metabolic reconfiguration fuels histone lactylation through enzymatic and non-enzymatic processes, providing a direct link between bioenergetics and chromatin modifications in skin pathology. Inhibition of key metabolic enzymes involved in lactate production effectively reduces H4K12la levels and attenuates disease severity in murine models, suggesting possible metabolic intervention points.

Importantly, the team employed integrative multi-omics strategies, including chromatin immunoprecipitation sequencing (ChIP-seq) for lactylated histones, transcriptomic profiling, and protein-protein interaction assays, to delineate the cascade initiated by H4K12la. These approaches unveiled that lactylation-enriched chromatin domains were associated with enhanced transcription of novel IL-17-responsive genes distinct from classical signaling mediators like ACT1 or NF-kB components. This transcriptional reprogramming results in an amplified keratinocyte-derived inflammatory milieu.

The translational implications of this research are immense. Current biologic treatments targeting IL-17 or its receptor have significantly improved psoriasis management but are not curative and can display variable efficacy. By defining a keratinocyte-intrinsic epigenetic mechanism that drives inflammation independently of traditional immune routes, new therapeutic targets emerge. Drugs designed to modulate histone lactylation or alter keratinocyte metabolic states could complement or augment existing therapies, potentially leading to more sustained remission.

Moreover, the discovery provides a conceptual framework for understanding how environmental and metabolic factors might exacerbate or trigger psoriatic flares through epigenetic alterations. Stressors such as hypoxia, altered glycolysis, and lactate accumulation are known to impact skin health but their causal roles were obscure until now. This study elegantly connects these dots, showcasing how environmental metabolites imprint on chromatin to rewire immune signaling in chronic disease.

The broader significance of histone lactylation in inflammatory disease is also suggested by these findings. Given that lactate levels rise in many pathological tissues, this epigenetic mechanism could play a role in other autoimmune disorders beyond psoriasis. Further work investigating histone lactylation dynamics in rheumatoid arthritis, inflammatory bowel disease, or multiple sclerosis may reveal conserved principles of metabolic-epigenetic immune regulation.

From a methodological standpoint, the study exemplifies how sophisticated mouse genetics, coupled with state-of-the-art epigenetic profiling and functional assays, can uncover previously hidden layers of immune regulation within non-immune cell types. The ability to manipulate histone lactylation in a cell-type specific manner underscores the precision now attainable in dissecting complex inflammatory pathways in vivo.

Looking forward, one key challenge will be to develop pharmacological agents capable of specifically modulating histone lactylation without broad off-target effects. Enzymes responsible for adding or removing lactyl groups remain poorly characterized compared to acetyltransferases or methyltransferases, necessitating intensive biochemical and structural studies. Nevertheless, targeted delivery methods and small molecules inspired by these pathways offer promising avenues for intervention.

In summary, this pioneering study redefines psoriasis pathogenesis by implicating keratinocyte-specific H4K12 lactylation as a crucial epigenetic switch that drives a non-canonical IL-17-dependent inflammatory pathway. This novel mechanism links metabolic alterations to immune dysregulation in the skin and challenges existing paradigms that position immune cells as sole instigators of disease. The work opens transformative prospects for epigenetic and metabolic therapies that may revolutionize treatment of psoriasis and other inflammatory conditions.

As the interplay between metabolism, epigenetics, and immunity rapidly expands as a field, discoveries such as these deepen our molecular understanding of chronic inflammation. They exemplify the power of interdisciplinary approaches to uncover unexpected cellular players and signaling networks underlying human disease. With continued research, the principles uncovered here may extend far beyond dermatology, illuminating universal strategies for modulating immune responses through metabolic epigenetics.

This seminal contribution underscores the urgency and promise of targeting cellular metabolism and epigenetic modifications in complex autoimmune diseases. The delineation of H4K12 lactylation in keratinocytes adds a potent new dimension to the epigenetic landscape of inflammation, one intricately tied to metabolic rewiring and immune crosstalk. Ultimately, this insight heralds a new era in understanding and treating psoriasis, guided by the subtle yet powerful marks written in our chromatin.

Subject of Research:
Keratinocyte-specific histone lactylation and its role in psoriasis pathogenesis through IL-17-dependent signaling.

Article Title:
Keratinocyte-specific H4K12 lactylation drives a non-canonical IL-17-dependent signaling in psoriasis progression in mice.

Article References:
Shen, X., Qiao, W., Yan, W. et al. Keratinocyte-specific H4K12 lactylation drives a non-canonical IL-17-dependent signaling in psoriasis progression in mice. Nat Commun 16, 8639 (2025). https://doi.org/10.1038/s41467-025-63791-7

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Psoriasis pathogenesis is a multifaceted interplay of immune dysregulation, keratinocyte hyperproliferation, and oxidative stress. Traditional treatments, while somewhat effective, often come with adverse effects or limited long-term efficacy. The imiquimod-induced murine model used in this research effectively mimics psoriatic pathology, providing a robust platform for preclinical evaluation. Of particular interest is the use of Curcuma longa extract, known commonly as turmeric, which contains curcuminoids celebrated for their anti-inflammatory, antioxidant, and immunomodulatory properties. Among these, curcumin and bisdemethoxycurcumin have attracted attention for their molecular mechanisms that inhibit pro-inflammatory pathways.

The integration of UVA exposure with these natural compounds represents an innovative therapeutic strategy. UVA radiation, known for its immunosuppressive and anti-proliferative effects on skin cells, has historically been used in phototherapy regimes for psoriasis. However, UVA alone carries risks such as photoaging and carcinogenesis. Combining it with Curcuma longa constituents may enhance therapeutic benefits while mitigating side effects, a hypothesis tested rigorously in this investigation.

In the study, BALB/c mice were subjected to imiquimod-induced psoriasis-like skin lesions, establishing a controlled environment to assess treatment efficacy. The researchers administered Curcuma longa extract, curcumin, or bisdemethoxycurcumin topically, followed by controlled UVA irradiation. Observations recorded over multiple treatment cycles revealed significant amelioration of skin lesions, reduction in erythema and scaling, and restored skin histology. This multidisciplinary approach combined phytochemistry, immunology, and photobiology, offering a nuanced understanding of how these treatments modulate skin inflammation at molecular and cellular levels.

Mechanistically, the study indicates that the combined treatments downregulated key inflammatory mediators, including tumor necrosis factor-alpha (TNF-α), interleukin-17 (IL-17), and interleukin-23 (IL-23). These cytokines are notoriously elevated in psoriasis and contribute substantially to the disease’s persistence and severity. Furthermore, oxidative stress markers were markedly decreased, suggesting that antioxidants present in Curcuma longa extracts synergize with UVA-induced effects to restore cellular redox balance. This sheds light on the possibility that such combination therapy not only dampens immune responses but also repairs oxidative damage that exacerbates psoriatic lesions.

Histopathological analyses enriched the findings by illustrating substantial attenuation of epidermal hyperplasia, parakeratosis, and immune cell infiltration characteristic of psoriasis. The serial application of curcuminoids with UVA altered the typical psoriatic architecture toward normalization. Notably, bisdemethoxycurcumin, though less studied than curcumin, demonstrated comparable potency, advocating for broader investigations into lesser-known curcuminoids as therapeutic agents.

Apart from the biochemical and histological improvements, the safety profile was promising. No significant adverse effects were observed in treated mice, contrasting favorably with many conventional psoriasis therapies that carry risks of systemic toxicity or immunosuppression. This underscores the potential for developing topical formulations combining Curcuma longa extracts and controlled UVA as a safer alternative or adjunct treatment, especially for patients contraindicated for aggressive systemic drugs.

The implications of this research extend beyond psoriasis. Chronic inflammatory and autoimmune skin disorders often share pathogenic pathways involving cytokine storms and oxidative stress. Thus, the principles uncovered here—leveraging plant-derived compounds alongside targeted phototherapy—may inform treatment innovations across dermatology. Moreover, the study emphasizes the importance of molecularly guided combination therapies that address multiple disease facets synergistically rather than monotherapeutic approaches.

Importantly, this research contributes to the expanding arena of natural product pharmacology integrated with modern medical technology. The bioavailability and skin penetration challenges often complicate the clinical translation of curcuminoids. Here, topical administration combined with UVA not only enhanced curcuminoid efficacy but may also facilitate deeper dermal absorption through photomodulation of skin barrier properties, a topic warranting deeper exploration in subsequent studies.

While the murine model provides compelling preliminary evidence, human clinical trials will be critical for validating safety, dosing, and efficacy. Psoriasis is a heterogeneous disease with genetic, environmental, and lifestyle influences; hence, personalized treatment protocols incorporating such combinatory regimens could revolutionize management. Furthermore, elucidating long-term effects, optimal timing of UVA exposure relative to compound application, and potential interactions with existing medications will be pivotal.

The study also prompts broader philosophical reflections on bridging traditional medicine and cutting-edge science. Turmeric’s historical and cultural significance converges here with rigorous scientific validation, exemplifying how ethnopharmacological wisdom can inspire novel biomedical approaches. In a healthcare landscape increasingly focused on integrative and patient-centered care, such research embodies the promise and challenge of harmonizing natural and synthetic modalities.

In a social context, psoriasis profoundly impacts quality of life, encompassing physical discomfort, stigmatization, and psychological distress. Accessible, non-invasive treatments derived from natural products could democratize care, alleviating socioeconomic barriers. This aligns with global health priorities promoting sustainable, affordable therapeutic strategies, particularly relevant in resource-constrained settings.

Future directions stemming from this research are manifold. Investigating the molecular docking of curcuminoids with key psoriasis-related receptors, examining gene expression profiles post-treatment, and exploring synergistic effects with other phototherapeutic wavelengths (e.g., UVB or visible light) could deepen mechanistic insights. Moreover, formulation science could optimize delivery vehicles, enhancing stability and controlled release of bioactive compounds.

Concomitantly, understanding how these treatments influence skin microbiota might uncover additional therapeutic mechanisms. Emerging evidence highlights the skin microbiome’s role in immune modulation and barrier integrity. It is plausible that Curcuma longa extract and UVA impact microbial communities, thereby contributing indirectly to disease mitigation.

Overall, this study represents a stride toward holistic, multifactorial treatment paradigms, stepping beyond symptomatic control toward underlying pathogenic correction. It fosters hope for patients and clinicians alike that natural compounds, scientifically harnessed and combined with advanced modalities like phototherapy, can yield transformative outcomes in chronic skin diseases such as psoriasis.

Subject of Research: Effects of combined treatment with Curcuma longa extract, curcumin, or bisdemethoxycurcumin and UVA radiation on imiquimod-induced psoriasis-like lesions in BALB/c mice.

Article Title: Effects of combined treatment with Curcuma longa extract, curcumin, or bisdemethoxycurcumin and UVA on imiquimod-induced psoriasis-like lesions in BALB/c mice.

Article References:
Kim, JW., Dorjsembe, B., Chang, PS. et al. Effects of combined treatment with Curcuma longa extract, curcumin, or bisdemethoxycurcumin and UVA on imiquimod-induced psoriasis-like lesions in BALB/c mice. Food Sci Biotechnol (2025). https://doi.org/10.1007/s10068-025-01940-w

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DOI: https://doi.org/10.1007/s10068-025-01940-w