PFHxS promotes renal fibrosis via PPARγ overactivation-dependent NLRP1 inflammasome-driven pyroptosis.

Perfluorohexanesulfonic acid (PFHxS) refers to a persistent environmental pollutant associated with declining kidney function. Notably, the underlying mechanisms of PFHxS remain unclear. Here, we demonstrate that chronic PFHxS exposure in mice induces renal fibrosis, as evidenced by collagen deposition, upregulated fibrotic markers, and impaired renal function. Mechanistically, we observed that PFHxS treatment resulted in increased protein levels of PPARγ and related genes, which further triggered lipid accumulation and mitochondrial ROS production in renal tubular cells. Pharmacological blockade or genetic knockdown of PPARγ markedly ameliorated PFHxS-induced lipid dysregulation, mitochondrial dysfunction, and fibrosis. Furthermore, RNA sequencing revealed that PFHxS activated the NLRP1 inflammasome, triggering Caspase-1-dependent pyroptosis, as validated by GSDMD cleavage. Notably, NLRP1 knockdown mitigated PFHxS-induced pyroptosis and fibrotic responses. Collectively, these findings highlight a novel mechanism whereby PFHxS drives renal fibrosis through PPARγ and the subsequent NLRP1 inflammasome-mediated pyroptosis, suggesting PPARγ and NLRP1 as promising therapeutic targets for PFHxS-associated kidney disease.