PM2.5 exacerbate nonalcoholic fatty liver disease through activating hepatocytes TXNIP/NLRP3/FoxO1 signaling pathway in ob/ob mice.

Growing evidence links fine particulate matter (PM2.5) exposure to nonalcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain unclear. Given the critical role of hepatocyte pyroptosis in NAFLD progression, this study investigated whether PM2.5 induces hepatocyte pyroptosis, thereby exacerbating NAFLD. In vivo, PM2.5 exposure (174.15 ± 0.086 μg/m3, 6 h/day, 4 weeks) worsened liver injury and steatosis in ob/ob mice. Both in-vivo and in-vitro experiments (using human hepatocytes treated with PM2.5 at 12.5-50 μg/mL for 24 h) demonstrated that PM2.5 increased oxidative stress, activated the TXNIP/NLRP3 pathway, and upregulated pyroptosis-related markers (GSDMD-N, Caspase-1, IL-1β, IL-18), leading to hepatic lipid accumulation through FoxO1. These effects were significantly attenuated in-vitro by inhibitors of mitochondrial ROS (Mito-TEMPO), Caspase-1 (VX-765), and GSDMD (disulfiram). Collectively, our study demonstrates that PM2.5 aggravates NAFLD by inducing mitochondrial ROS-dependent hepatocyte pyroptosis, providing new insights into the toxic mechanisms of PM2.5-associated liver disease.