Psoriasis is a chronic skin disease driven by skin inflammation and abnormal subcutaneous blood vessels. Yinxie Granules (YXKL) is a clinically effective traditional Chinese medicine (TCM) formula that has shown promise in psoriasis treatment, but its pharmacological mechanisms and material basis remain unclear, limiting its clinical application and co-administration with other drugs. In this study, we explored the mechanism and active components of YXKL in the treatment of psoriasis using patient samples, IMQ-induced psoriatic mice, zebrafish, and in vitro assays. We discovered that YXKL alleviated skin inflammation and restored the skin barrier by reducing M1 macrophage/Th17 infiltration, lowering pro-inflammatory cytokines (IL-6, IFN-β, IL-23, IL-17), and increasing loricrin expression. Mechanistically, we identified a dynamic transition in STING signaling during psoriasis progression. Both the STING/IRF3 and STING/NF-κB pathways were activated in moderate psoriasis, while only the STING/NF-κB pathway was hyperactivated in severe disease. YXKL specifically targeted the STING/NF-κB pathway to mitigate inflammation and vasculopathy but had no significant impact on the upstream regulators, including TRAF6, LKB1, AMPK, and ULK1. Quercetin and kaempferol were identified as the primary STING-modulating components in YXKL, binding to STING proteins and inhibiting downstream pathway activation. These flavonoid components mediate the anti-psoriatic effects of YXKL by simultaneously suppressing skin inflammation and angiogenesis while enhancing vascular integrity through STING inhibition in both keratinocytes and endothelial cells. Our results elucidated the molecular basis of YXKL for psoriasis treatment, highlighting STING/NF-κB as a pivotal therapeutic target in mitigating psoriasis development and providing natural candidate compounds as potential STING inhibitors.
