Celastrol disrupts the inflammatory feedback loop driven by Tenascin-C⁺ fibroblast subtype in psoriasis: Insights from single-cell RNA sequencing and experimental validation.

Abstract

BACKGROUND AND OBJECTIVE: Psoriasis is a chronic inflammatory skin disease involving abnormal interactions among inflammation-related cells. Celastrol, a natural compound with broad anti-inflammatory activity, has shown therapeutic potential in psoriasis. However, its mechanism in regulating multicellular interaction networks remains relatively limited. This study aimed to explore how celastrol modulates intercellular interactions in psoriasis. METHODS: Single-cell transcriptomic data from three mouse groups-healthy controls, imiquimod (IMQ)-induced psoriasis-like model, and celastrol-treated-were obtained from the GEO database. CellChat analysis, differential gene expression, GSEA, and transcription factor analyses were conducted. An inflammatory feedback loop mediated by TNC⁺ fibroblasts was proposed based on these results and literature evidence. An IMQ-induced psoriasis-like mouse model was then established in BALB/c mice and treated with different doses of celastrol or methotrexate (MTX). Therapeutic efficacy was assessed by PASI scoring, H&E staining, and ELISA. Immunohistochemistry and immunofluorescence were used to validate the inhibitory effect of celastrol on this loop. Subsequently, functional validation was performed using NIH-3T3 fibroblasts to assess TNC-mediated signaling and its modulation by celastrol. RESULTS: We identified a TNC⁺ fibroblast-driven inflammatory feedback loop in psoriatic skin. These fibroblasts secreted chemokines (Ccl2, Cxcl12) and pro-inflammatory cytokines (Il6, Saa3), interacting with myeloid immune cells to activate the TNF-NF-κB and IL-6-JAK-STAT3 pathways. Both in vitro and in vivo experiments confirmed that celastrol disrupted this loop and alleviated IMQ-induced psoriasis-like skin inflammation by suppressing the expression of multiple key proteins. CONCLUSION: Celastrol alleviates psoriasis by disrupting the TNC⁺ fibroblast-mediated inflammatory feedback loop via multi-target modulation, offering new insights into its therapeutic mechanism and clinical potential.