Bixin prevents tubulointerstitial fibrosis in hyperuricemic nephropathy via promoting PPARγ-NLRP3 interaction

Hyperuricemic nephropathy (HN), characterized by severe inflammation-induced tubulointerstitial fibrosis (TIF), has emerged as a common subtype of chronic kidney disease. Bixin, a carotenoid extracted from the seeds of Bixa orellana, recently garnered attention for its anti-inflammatory and anti-fibrotic activities, though its potential effects in HN remain unexplored. In this study, expression of transcription factor (TF) PPARγ was negatively correlated with fibrosis and NLRP3 inflammasome-mediated inflammation in uric acid (UA)-treated human proximal tubule cell line (HK2) and kidneys from HN mice. Notably, PPARγ served as a common target of HN and bixin, and showed a unique downregulated trend among various TFs in kidneys from HN mice. Bixin significantly upregulated PPARγ expression, while attenuating fibrotic changes and NLRP3 inflammasome in tubular cells under HN and UA conditions. Moreover, PPARγ silencing in HK2 cells induced fibrotic and NLRP3 inflammasome-mediated inflammatory alterations, and counteracted the protective effects of bixin in UA conditions. Mechanistically, bixin targets and stabilizes PPARγ, which binds NLRP3 to block its oligomer formation, thereby inhibiting inflammasome assembly. Therefore, this study not only highlights the therapeutic potential of bixin in HN management via promoting PPARγ-NLRP3 interaction to break the vicious inflammation-TIF cycle, but also establishes PPARγ as a promising pharmacological target for HN intervention.