Abstract

Bergenin, a plant-derived PPARγ agonist, alleviates psoriasis by selectively targeting pathogenic γδT17 cells. • Bergenin-activated PPARγ triggers K248-ubiquitination of PROX1, revealing a novel proteolytic mechanism in psoriasis therapy. • Inhibiting fatty acid oxidation specifically suppresses γδT17, but not Th17, cell activation in psoriasis. • Skin γδT cells highly express PPARγ and PROX1, defining a precise cellular target for plant-based intervention. Background Psoriasis, a persistent inflammatory skin ailment, is distinguished by aberrant γδT17 cell activation. The primary active compound in Bergenia purpurascens , bergenin (Ber), a natural peroxisome proliferator-activated receptor-gamma ( PPARγ) agonist, appears to exhibit anti-γδT17 cell activation effects; nevertheless, its therapeutic efficacy for psoriasis remains to be elucidated. Purpose To investigate the effects of Ber on psoriasis and to explore its anti-psoriatic mechanisms of action. Methods The effects of Ber activation of PPARγ on psoriasis and its γδT17 cells were assessed both in vitro and in vivo. The PPARγ and γδT17 cells activation in psoriatic patients and an imiquimod-induced C57BL/6 mouse model were evaluated. The fatty acid oxidation (FAO) was examined, and prospero homeobox protein 1 (PROX1) degradation and its impact on IL17A transcription were determined by Seahorse metabolic analysis, Co-IP, and ChIP-qPCR. Results Ber alleviated psoriatic dermatitis by reducing γδT17 activation in a PPARγ-dependent manner, an effect abolished by adoptive transfer of activated γδT17 cells. Mechanistically, Ber-induced PPARγ activation enhanced its E3 ligase function, promoting K248-linked ubiquitination and degradation of PROX1. This inhibited CPT1-driven FAO, diminished histone H3K9/27 acetylation at the IL17A promoter, and repressed IL-17A production. Conclusion Ber exerts anti-psoriatic effects by activating PPARγ to prompt ubiquitin-mediated PROX1 degradation, thereby inhibiting FAO and IL-