Enhanced BEST2 expression in keratinocytes alleviates psoriatic inflammation.

BEST2, a member of the Bestrophin gene family, functions as an anion channel involved in regulating intracellular ion concentrations. It has also been implicated in the pathogenesis of various inflammatory conditions such as colonic inflammation. However, its role in psoriasis remains largely unexplored. In this study, we investigated the role and underlying mechanisms of BEST2 in TP (Triptolide)- treated psoriasis, using the M5-induced HaCaT cell in vitro and the imiquimod (IMQ)-induced psoriasis mouse model. Our findings demonstrated that TP effectively inhibited M5-induced hyperproliferation and the inflammatory response in HaCaT cells by significantly upregulating BEST2 expression. This upregulation in turn inhibits the activation of the JAK2/STAT3 signaling pathway for inflammatory cytokies and promotes the cell cycle arrest at the G-G phase. Furthermore, topic administration of TP effectively alleviated skin erythema, scaling, and thickness in the IMQ-induced mouse model, along with a reduction in PASI scores and histopathological alterations. Notably, no significant damage to the liver, kidney, or testicular tissues was observed in mice following topic TP administration, indicating a higher safety profile compared with other systemic injections. In conclusion, our study highlights the significant role of BEST2 in the pathogenesis of psoriasis and suggests that targeting BEST2 could represent a promising therapeutic strategy.