Quercetin attenuates skin inflammation and fibrosis in systemic sclerosis by targeting the RELA/c-Jun axis to suppress th17 cell responses

Background Aberrant Th17 cell activation and interleukin-17 (IL-17) production drive skin inflammation and progressive fibrosis in systemic sclerosis (SSc). Identifying small molecules that can precisely modulate these pathogenic T cell responses is crucial for developing novel SSc therapies. Methods We utilized primary CD4 + T cells isolated from SSc patients and a bleomycin-induced SSc mouse model to evaluate the immunomodulatory effects of quercetin. Direct molecular target engagement was rigorously validated using Drug Affinity Responsive Target Stability (DARTS) and Cellular Thermal Shift Assay (CETSA). Results In patient-derived CD4 + T cells, quercetin treatment significantly suppressed the secretion of pro-inflammatory cytokines, including IL-17A and IFN-γ. Mechanistically, we demonstrated through DARTS and CETSA that quercetin directly binds to and stabilizes transcription factors RELA (p65) and c-Jun. This interaction effectively inhibited their phosphorylation and subsequent nuclear translocation, thereby dampening the IL-17 signaling cascade. In vivo , oral administration of quercetin significantly attenuated skin thickness, collagen deposition, and myofibroblast activation in SSc mice. Conclusion Our findings identify the RELA/c-Jun axis as a critical target for modulating T cell pathogenicity in SSc and suggest that quercetin holds therapeutic potential as an immunometabolic modulator to alleviate skin fibrosis.