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Celastrol disrupts the inflammatory feedback loop driven by Tenascin-C⁺ fibroblast subtype in psoriasis: Insights

Yupeng Ma¹, Xue Zhang², Xinhong Chen¹

¹School of Gongli Hospital Medical Technology, University of Shanghai for Science and Technology, Shanghai 200093, China.

Phytomedicine : International Journal of Phytotherapy and Phytopharmacology

|February 28, 2026

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.

Insights

Celastrol effectively treats psoriasis by disrupting a TNC⁺ fibroblast inflammatory loop. This natural compound modulates intercellular communication, offering a novel therapeutic approach for this chronic skin condition.

Area of Science:

Immunology
Dermatology
Pharmacology

Background:

Psoriasis is a chronic inflammatory skin disease characterized by aberrant multicellular interactions.
Celastrol, a natural compound, exhibits anti-inflammatory properties but its mechanism in psoriasis remains unclear.
Understanding celastrol's modulation of intercellular networks is crucial for its therapeutic application.

Purpose of the Study:

To investigate how celastrol affects intercellular communication in psoriasis.
To identify key cellular players and pathways involved in celastrol's therapeutic effect.
To explore the potential of celastrol as a psoriasis treatment by targeting specific feedback loops.

Main Methods:

Single-cell transcriptomics and CellChat analysis of healthy, psoriasis-like, and celastrol-treated mouse models.
In vivo validation using an imiquimod (IMQ)-induced psoriasis-like mouse model treated with celastrol or methotrexate (MTX).
In vitro studies with NIH-3T3 fibroblasts to assess TNC-mediated signaling and celastrol's impact.

Main Results:

A TNC⁺ fibroblast-driven inflammatory feedback loop was identified in psoriatic skin.
Celastrol disrupted this loop by suppressing chemokine and cytokine secretion from fibroblasts.
Celastrol alleviated psoriasis-like skin inflammation by inhibiting key protein expression and inflammatory pathways (TNF-NF-κB, IL-6-JAK-STAT3).

Conclusions:

Celastrol alleviates psoriasis by disrupting the TNC⁺ fibroblast-mediated inflammatory feedback loop.
The therapeutic mechanism involves multi-target modulation of intercellular interactions.
Celastrol demonstrates significant therapeutic potential for psoriasis treatment.

Read full analysis

Keywords:

Celastrol Cell-cell interactions Fibroblasts Inflammatory loop Psoriasis Single-cell RNA sequencing

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