Psoriasis, a chronic inflammatory skin disease characterized by oxidative stress and dysregulated immunity, necessitates innovative therapies to overcome the limitations of conventional treatments. This study introduces cobalt phosphide nanoparticles deposited on carbon polyhedral frameworks (CoP-C PFs) as a multifunctional nanoplatform integrating enzyme-mimicking catalysis and photothermal activity for synergistic psoriasis management. CoP-C PFs exhibit superior catalytic efficiency, with low Michaelis-Menten constants (e.g., K m = 0.26 mM for H 2 O 2 decomposition), enabling potent reactive oxygen species (ROS) scavenging to alleviate oxidative damage in RAW264.7 macrophages and HaCaT keratinocytes. Under 808 nm near-infrared irradiation, CoP-C PFs exhibit a high photothermal conversion efficiency of 68.6%, enabling precise control of the local temperature to generate localized hyperthermia to enhance catalytic ROS elimination and antibacterial activity. In an imiquimod-induced psoriatic murine model, CoP-C PFs alleviated inflammation by restoring redox balance, suppressing CD3 + T cell/F4/80 + macrophage infiltration, modulating IL-17A/IL-23 and TNF-α/NF-κB pathways, and promoting M2 macrophage polarization (increased CD206 + /CD68 + ratio), resulting in epidermal normalization and reduced abnormal keratinization without organ toxicity, underscoring effectiveness and biosafety. By integrating photothermal enhancement with multienzyme catalysis, this “all-in-one” nanozyme platform enables dual regulation of oxidative stress and immune microenvironment, offering a promising therapeutic strategy for psoriasis and other inflammatory skin disorders.

Atopic dermatitis (AD) is characterized by type-2 inflammation, dermal mast-cell (MC) infiltration and progressive dermal fibrosis, but the stromal drivers remain unclear. Using the MC903-induced AD-like mouse model, we show that dermal white adipose tissue (dWAT) undergoes rapid lipolysis and reactive fibrosis concurrent with MC accumulation and activation within dWAT. Single-cell RNA-seq and adipocyte-lineage tracing revealed that MC903 applications triggered mature adipocytes to lose lipids and acquire a F3 + C/EBPδ + inflammatory preadipocyte (inf. pAds) phenotype that secrete MC chemokines, SCF and CXCL12. Neutralization or fibroblast-specific deletion of either chemokine abolished MC recruitment, adipocyte loss and collagen deposition, whereas MC depletion prevented inf. pAd expension, revealing a self-amplifying inflammatory–fibrotic loop between adipocytes and MCs. In vitro, MC-conditioned medium or recombinant IL4/IL13/TGFβ induced adipocyte lipolysis and F3⁺C/EBPδ⁺ pre-adipocyte markers; combined STAT6 and TGFβ inhibition abrogated this reprogramming. scRNAseq and immunostaining analysis of human AD lesional skin identified F3 + C/EBPδ + dermal fibroblasts that transcriptionally mirror murine inf. pAds, express SCF/CXCL12, and co-localize with MCs. Human adipocytes respond to IL4/IL13/TG-β by lipolysis and acquisition of fibroblast-like phenotype. This study reveals a previously unrecognized adipocyte-to-fibroblast conversion pathway that fuels mast-cell recruitment and dermal fibrosis in AD, offering a novel mechanistic framework and a therapeutic entry point aimed at blocking adipocyte dedifferentiation or its downstream SCF/CXCL12 signals to simultaneously halt inflammation and fibrotic remodeling.

Double-stranded RNA (dsRNA) and reactive oxygen species (ROS) contribute to the exacerbation of skin inflammatory diseases such as psoriasis and atopic dermatitis. While antioxidant strategies have been extensively explored, approaches to neutralize pathogenic dsRNA remain limited. Here, we show that Mo90Ce10, a cerium-doped polyoxometalate, concurrently targets dsRNA and ROS to mitigate cutaneous inflammation. In vitro, Mo90Ce10 scavenges ROS and suppresses type I interferon responses by directly binding dsRNA through its oxygen-rich, hydrogen bond-forming surface. Its structural template, {Mo154}, exhibits weaker activity. In vivo, Mo90Ce10 reduces disease severity, dsRNA-induced inflammation, ROS burden, and neutrophil infiltration. Leveraging its negative charge and self-assembly properties, we further develop a transdermal platform by complexing Mo90Ce10 with the cationic peptide TD-1 and co-loading methotrexate, thereby enhancing drug penetration andtherapeutic efficacy while reducing recurrence. Together, these findings establish Mo90Ce10 as a multifunctional modulator of dsRNA- and ROS-driven inflammation and a promising transdermal delivery platform for inflammatory diseases.

IntroductionAllergic contact dermatitis (ACD) and atopic dermatitis (AD) are driven by distinct T cell programs, and safe long-term topical therapies remain limited. Dermal fibroblasts (dFBs) have emerged as active immunomodulators, but whether they can be therapeutically targeted remains unexplored.MethodsHere we developed MDI1228, a novel topical pan‑JAK inhibitor with nanomolar potency against JAK1/2/3/TYK2 (IC₅₀ 0.11-0.85 nM) and high selectivity. MDI1228 was evaluated in DNFB‑induced ACD and MC903‑induced AD mouse models, as well as in primary mouse and human cell‑based assays.ResultsTopical MDI1228 ameliorated both ACD and AD in mice, reducing T cell infiltration and cytokine production. Mechanistically, MDI1228 not only directly inhibited T cell activation and cytokine production but also disrupted fibroblast‑T cell crosstalk by reducing dFB‑derived chemokine expression. Single‑cell transcriptomics identified dFBs as the primary source of CXCL9/10 in ACD and CCL2 in AD. Conditioned medium and neutralization experiments demonstrated that CXCL9/10‑CXCR3 and CCL2‑CCR2 signaling axes contribute to T cell polarization in a context‑dependent manner. Compared with glucocorticoids, prolonged topical application of MDI1228 showed minimal systemic toxicity and preserved tissue homeostasis.DiscussionThese findings identify dFBs as a central therapeutic node and demonstrate that MDI1228, by directly targeting T cells and disrupting dFB‑derived chemokine axes via JAK inhibition, offers a potent and safe topical treatment for both ACD and AD.

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl4 and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Metabolic dysfunction-associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction-associated steatotic liver disease, is characterized by significant hepatic fibrosis and inflammation. The pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist IVA337 (lanifibranor) has shown potential as an anti-MASH therapeutic, although its mechanisms of action remain incompletely understood. This study explores the effects and mechanisms of IVA337 using two distinct MASH models: two-dimensional (2D) primary human hepatic stellate cells (HSCs) stimulated with transforming growth factor β1 (TGF-β1), and three-dimensional (3D) liver spheroids comprising primary hepatocytes, HSCs, and non-parenchymal cells. In TGF-β1-stimulated HSCs, IVA337 effectively suppressed the expression of fibrosis-related genes, including PAI1, COL1A1, and ACAT2, as well as the inflammatory gene IL6. 3D mouse and human liver spheroid models of MASH, characterized by elevated fibrotic gene expression, were established. IVA337 treatment not only attenuated fibrotic gene expression but also restored lipid content in the MASH spheroids, as evidenced by BODIPY staining. Immunostaining further confirmed a reduction in α-smooth muscle actin and collagen 1 levels after IVA337 treatment. Bulk RNA sequencing and Gene Ontology analysis revealed several lipid metabolism-related genes as key effectors downstream of IVA337. In addition, IVA337 modulated multiple signaling pathways, including IL-17, tumor necrosis factor, NF-κB, phosphatidylinositol 3 kinase/protein kinase B, and mitogen-activated protein kinase. Collectively, these findings show that IVA337 effectively mitigates fibrosis development in both 2D and 3D MASH models by restoring lipid homeostasis and regulating crucial fibrotic and inflammatory pathways.

The immune response of the skin to danger signals involves rapid recruitment of neutrophils, but their excessive accumulation leads to inflammatory skin diseases, such as psoriasis; however, the mechanisms governing their initiation and resolution are poorly understood. Here, we revealed a dynamic immunoregulatory role of dermal white adipose tissue (dWAT) in the progression and resolution of neutrophilic skin inflammation in an imiquimod-induced psoriasis mouse model. During inflammation onset, dWAT repopulates PDGFRA+ preadipocytes (pAds), which secrete CXCL1 and SAA3, attracting and activating CXCR2+ neutrophils. These neutrophils further activate pAds through the IL-1R-NFκB-C/EBPδ pathway, establishing a self-sustaining inflammatory loop. Paradoxically, prolonged IL-1β signaling triggers PPARγ-dependent adipogenesis, transitioning pAds into anti-inflammatory early adipocytes that resolve neutrophilic inflammation via lipid mediators. Inhibition of adipogenesis, via pharmacological or genetic inhibition of PPARγ, disrupts the formation of early adipocytes, prevents neutrophil regression, and exacerbates inflammation. Analysis of human psoriatic cells revealed a C/EBPδ+ dermal fibroblast (dFB) subpopulation enriched with preadipocytes, the IL-1 pathway, and inflammatory gene signatures. Furthermore, transcriptomic analyses revealed a negative correlation between the neutrophil-related inflammatory response and the dermal lipogenesis response in generalized pustular psoriasis. Together, our findings reveal the dual role of dWAT: PDGFRA+ pAds initiate inflammation via CXCL1/IL-1β crosstalk with neutrophils, whereas PPARγ-driven adipogenesis resolves this process through lipid mediators. This work establishes dWAT as a critical immunomodulatory hub and proposes adipogenic reprogramming of proinflammatory fibroblasts or topical delivery of early adipocyte lipids as innovative therapies for neutrophil-driven skin diseases, such as psoriasis and ulcers. Our study uncovers a dynamic immunoregulatory role of dermal white adipose tissue (dWAT) in the progression and resolution of neutrophilic skin inflammation in an imiquimod-induced psoriatic mouse model. Initially, dWAT undergoes lipolysis and expands preadipocytes (pAds) secreting CXCL1/SAA3 to recruit neutrophils, which amplify inflammation via IL1β and activate pAds through the IL1-NFκB-C/EBPδ pathway. Prolonged IL1β exposure triggers PPARγ-dependent differentiation of pAds into early adipocytes, producing anti-inflammatory lipids that resolve neutrophilic inflammation. We also observed a negative correlation between neutrophil-related inflammatory response with dermal lipogenesis is also observed in human psoriasis. These findings highlight dWAT as an immunomodulatory hub, suggesting adipogenic reprogramming or lipid delivery as novel psoriasis therapies.

Disrupted N-6-methyladenosine (m(6)A) modification modulates various inflammatory disorders. However, the role of m(6)A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m(6)A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of Mettl3 in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m(6)A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m(6)A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m(6)A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m(6)A modification-lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m(6)A modulators to attenuate inflammatory skin diseases.

Psoriasis is a chronic inflammatory skin condition characterized by erythematous plaques with white scales. Its pathogenesis is closely linked to oxidative stress and an imbalance in Th1/Th2 immune responses. Current treatments for psoriasis, such as topical agents, systemic therapies and phototherapy, frequently fail to achieve complete remission in clinical settings. Monomethyl fumarate (MMF), which has been approved by the US Food and Drug Administration in 2020 for multiple sclerosis, has demonstrated efficacy in psoriasis management. Additionally, our previous studies have identified aluminum ions as beneficial in psoriasis treatment. This present study investigates the combined therapeutic effects of MMF and aluminum ions and observed that the combination treatment achieves superior efficacy compared to either treatment alone in a psoriasis mouse model through the modulation of the Nrf2/NF-κB signaling pathway, as demonstrated in cellular models. The combination first activates Nrf2 nuclear translocation and induces antioxidant gene expression, followed by the inhibition of NF-κB nuclear translocation and phosphorylation, which reduces Th1 cytokine production and cellular chemotaxis. Concurrently, the treatment elevates Th2 cytokine secretion, thereby increasing the anti-inflammatory response in HaCaT cells. Overall, these findings support the MMF and aluminum ions combination (MMFAL) as a potential therapeutic strategy for psoriasis, effectively diminishing inflammation and oxidative stress.

Aberrant activation of dermal fibroblasts during wound healing often leads to debilitating fibrotic changes in the skin, such as scleroderma and keloids. However, the underlying cellular and molecular mechanisms remain elusive. Here, we established a wound-induced skin fibrosis (WISF) mouse model in mature adult mice, characterised by excessive deposition of collagen bundles, loss of dermal adipocytes, and enrichment of DPP4+Ly6A+THY1+ hypodermal interstitial adipocyte progenitors (HI-APs) and pericytes, resembling human fibrotic skin diseases. This WISF model exhibited an age-dependent gain of fibrotic characteristics, contrasting with the wound-induced hair neogenesis observed in younger mice. Through comprehensive analyses of the WISF, we delineated a trajectory of fibroblast differentiation that originates from HI-APs. These progenitors highly expressed several extracellular matrix (ECM) genes and exhibited a TGFβ pathway signature. TGFβ was identified as the key signal to inhibit the adipogenic potential and maintain the fibrogenic potential of dermal APs. Additionally, administering a TGFβ receptor inhibitor to wound scar reduced the abundance of ECM-producing APs. Finally, analysis of human scleroderma skin tissues revealed a negative correlation between the expression of AP-, ECM-, and TGFβ pathway-related genes and PPARG. Overall, this study establishes a wound-induced skin fibrosis mouse model and demonstrates that TGFβ-mediated blockage of HI-AP differentiation is crucial for driving fibrotic pathology. Targeting HI-APs and adipogenesis may provide novel avenues for developing disease-modifying therapies for fibrotic skin diseases.

The skin’s immune response to danger signals involves rapid recruitment of neutrophils, but their excessive accumulation leads to inflammatory skin diseases, such as psoriasis, and how skin resident cells tolerate neutrophilic inflammation is poorly understood. Dermal white adipose tissue (dWAT) is an emerging component of the skin's immune barrier, but its role in controlling skin inflammation remains under-studied. Here, using an imiquimod-induced psoriasis mouse model, we observed a dynamic coupling between dermal adipogenesis, neutrophil infiltration and regression. During the early inflammatory phase, dWAT repopulates with PDGFRA+ preadipocytes that secrete CXCL1 and SAA3, attracting and activating CXCR2+ neutrophils. These neutrophils further activate preadipocytes through IL1β-IL1R signaling, establishing a self-sustaining inflammatory loop. Prolonged activation of pAds triggers PPARγ-dependent adipogenesis, leading to the formation of early adipocytes that secrete lipids exerting potent anti-inflammatory activity against myeloid cells, thereby aiding in inflammation resolution. Inhibition of adipogenesis, via targeted inhibition of PPARγ, through either pharmacological or genetic approaches, disrupts the formation of early adipocytes and prevents neutrophil regression and inflammation resolution. Analysis of human psoriatic cells identified a dFB subpopulation enriched with preadipocyte, IL1-pathway, and inflammatory gene signatures. Furthermore, transcriptomic analyses revealed a negative correlation between neutrophil-related inflammatory response with dermal adipogenesis response in generalized pustular psoriasis. Together, this study highlights the distinct roles of adipogenic fibroblasts and early adipocytes in initiating and resolving skin inflammation and suggests that promoting the differentiation of proinflammatory fibroblasts into anti-inflammatory early adipocytes could open avenues for the treatment of neutrophil-related inflammatory skin diseases, such as psoriasis and ulcers.

Allergic contact dermatitis (ACD), a prevalent inflammatory skin disease, is elicited upon repeated skin contact with protein-reactive chemicals through a complex and poorly characterized cellular network between immune cells and skin resident cells. Here, single-cell transcriptomic analysis of the murine hapten-elicited model of ACD reveals that upon elicitation of ACD, infiltrated CD4 + or CD8 + lymphocytes were primarily the IFNγ-producing type 1 central memory phenotype. In contrast, type 2 cytokines (IL4 and IL13) were dominantly expressed by basophils, IL17A was primarily expressed by δγ T cells, and IL1β was identified as the primary cytokine expressed by activated neutrophils/monocytes and macrophages. Furthermore, analysis of skin resident cells identified a sub-cluster of dermal fibroblasts with preadipocyte signature as a prominent target for IFNγ + lymphocytes and dermal source for key T cell chemokines CXCL9/10. IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. Furthermore, targeted deletion of Ifngr1 in dermal fibroblasts in mice reduced Cxcl9/10 expression, dermal infiltration of CD8 + T cell, and alleviated ACD inflammation in mice. Finally, we showed that IFNγ + CD8 + T cells and CXCL10-producing dermal fibroblasts co-enriched in the dermis of human ACD skin. Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis.

Dermal fibroblasts (dFBs) defend against deep bacterial skin infections by differentiating into preadipocytes (pAds) that produce the antimicrobial peptide cathelicidin; this differentiation is known as the dermal reactive adipogenesis response. However, the role of dFBs in fungal infection remains unknown. Here, we found that cathelicidin-producing pAds were present in high numbers in skin lesions from patients with cutaneous Candida granulomas. Second, we showed that dermal Candida albicans (C. albicans) infection in mice robustly triggered the dermal reactive adipogenesis response and induced cathelicidin expression, and inhibition of adipogenesis with pharmacological inhibitors of peroxisome proliferator-activated receptor γ (PPARγ) impaired skin resistance to C. albicans. In vitro, C. albicans products induced cathelicidin expression in pAds, and differentiating pAds markedly suppressed the growth of C. albicans by producing cathelicidin. Finally, we showed that C. albicans induced an antimicrobial response in pAds through the FGFR-MEK-ERK pathway. Together, our data reveal a previously unknown role of dFBs in the defense against skin infection caused by C. albicans.

Dermal white adipose tissue (dWAT) has been recently recognized as an indispensable deep skin layer with important non-metabolic functions in regulating hair cycling, wound regeneration, and defense against bacterial infection. We have previously shown that bacterial invasion to skin dermis triggers a reactive adipogenesis response, but whether commensal bacteria plays a role in dermal adipogenesis and whether this cross-talk between bacteria and dWAT is involved in hair cycling have not been investigated. Here, by investigating germ-free mice and/or by topical application of antibiotics, we found that depletion of skin microbiota led to a reduction in the adipogenic potential of dermal fibroblasts, reduced dWAT volume, and a blockage in depilation-induced dermal adipogenesis and onset of hair cycling. Furthermore, intradermal injection of conditioned medium from differentiating adipocytes restored the depilation-induced hair neogenesis in the microbiota-depleted mice. Finally, we showed that bacterial products derived from skin commensal bacteria enhanced the adipogenic potential of dermal fibroblasts, and this process was mediated by myeloid differentiation factor 88 (Myd88), a key adaptor signaling molecule downstream of TLR signaling pathway. Together, our results indicate that commensal bacteria may promote hair growth by triggering dermal adipogenesis through innate immune mechanism, and bacterial products may be therapeutic for skin disorders characterized by lipodystrophy and hair follicle dysfunction.