Polyphyllin I mitigates psoriasiform inflammation and prevents relapse by modulating CLEC7A and inhibiting pyroptosis.

Abstract

BACKGROUND: Psoriasis remains a significant global health concern, with a lack of effective treatments, thus driving the need for innovative therapeutic approaches. Polyphyllin I (PPI) has demonstrated potential in mitigating inflammation and controlling cellular growth, although the precise mechanisms underlying its effects and its full therapeutic capabilities in psoriasis require further investigation. PURPOSE: To assess the efficacy of PPI and examine its role in treating psoriasis and preventing relapse. METHODS: We designed both animal and cell-based experiments to investigate the efficacy and anti-inflammatory effects of PPI in treating psoriasis and preventing disease recurrence. To elucidate the potential mechanisms underlying PPI's therapeutic effects in psoriasis, we employed an integrative multi-omics approach combining bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) analysis. RESULTS: PPI inhibited abnormal keratinocyte proliferation, regulating the cell cycle and pyroptosis. In murine models of psoriasis and its relapse, PPI notably reduced symptoms such as erythema, scaling, epidermal thickening, and elevated inflammatory markers, including interleukin (IL)-17, IL-23, and IL-6 in peripheral blood, thereby confirming its therapeutic and relapse-prevention capabilities. Bioinformatics analysis indicated that PPI modulated C-Type Lectin Domain Containing 7A (CLEC7A) and inflammatory immune signaling pathways, and highlighted CLEC7A as a potential target for psoriasis prevention and treatment. CLEC7A+ keratinocytes engaged fibroblasts via the Kallikrein (KLK) 8 - coagulation factor II thrombin receptor (F2R) pathway. PPI treatment significantly downregulated the expression of CLEC7A, KLK8, and F2R in psoriasis mice. Notably, the combination of siRNA targeting CLEC7A (si-CLEC7A) and high-dose PPI group (PPI-H) further suppressed the expression of key inflammatory cytokines (IL-17, IL-23A, IL-6), proteases (KLK8, F2R), and pyroptosis-associated proteins (Caspase-1, GSDMD, IL-1β, and IL-18) of psoriasis. CONCLUSION: PPI may exert therapeutic potential in treating psoriasis and preventing disease recurrence by downregulating the CLEC7A/KLK8/F2R signaling axis, thereby attenuating inflammatory responses and pyroptosis.