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 (PM_2.5) 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 PM_2.5 induces hepatocyte Pyroptosis, thereby exacerbating NAFLD. In vivo, PM_2.5 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 PM_2.5 at 12.5-50 μg/mL for 24 h) demonstrated that PM_2.5 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 PM_2.5 aggravates NAFLD by inducing mitochondrial ROS-dependent hepatocyte Pyroptosis, providing new insights into the toxic mechanisms of PM_2.5-associated liver disease.

Fine particulate matter; Nonalcoholic fatty liver disease; TXNIP/NLRP3/FoxO1 signaling pathway; pyroptosis.