Quercetin attenuates skin inflammation and fibrosis in systemic sclerosis by targeting the RELA/c-Jun axis

Aberrant activation of Th17 cells and excessive production of interleukin-17 (IL-17) are central drivers of skin inflammation and progressive fibrosis in Systemic Sclerosis (SSc). Current standard-of-care treatments often fall short in effectively modulating these pathogenic T cell responses, leaving a significant unmet need for novel therapeutic strategies. Identifying small molecules capable of precisely targeting the underlying mechanisms of Th17 cell pathogenicity is crucial for developing more effective interventions for this debilitating autoimmune disease.

Researchers investigated quercetin's immunomodulatory effects using primary CD4+ T cells isolated from SSc patients and a bleomycin-induced SSc mouse model. In vitro, patient-derived CD4+ T cells were treated with quercetin to assess cytokine secretion. For in vivo studies, mice with bleomycin-induced SSc received oral administration of quercetin. Direct molecular target engagement was validated using Drug Affinity Responsive Target Stability (DARTS) and Cellular Thermal Shift Assay (CETSA). Primary endpoints included cytokine levels, skin thickness, collagen deposition, and myofibroblast activation.

In CD4+ T cells from SSc patients, quercetin treatment significantly suppressed the secretion of pro-inflammatory cytokines, including IL-17A and IFN-γ. Mechanistically, DARTS and CETSA assays demonstrated that quercetin directly binds to and stabilizes the transcription factors RELA (p65) and c-Jun. This direct interaction effectively inhibited their phosphorylation and subsequent nuclear translocation, thereby dampening the IL-17 signaling cascade. This suggests a precise molecular mechanism for its anti-inflammatory action. In vivo, oral administration of quercetin significantly attenuated key markers of SSc progression. > Quercetin significantly attenuated skin thickness, collagen deposition, and myofibroblast activation in the SSc mouse model. These findings highlight the RELA/c-Jun axis as a critical target for modulating T cell pathogenicity in SSc.