PM _2.5 Induced Iron Accumulation-Associated Hepatocyte Toxicity and Mice Liver Injury via Activation of Ferroptosis and Pyroptosis

Increasing evidence revealed a significant relationship between the fine particulate matter (PM_2.5) exposure and the incidence of liver diseases. The contributions of ferroptosis and pyroptosis were recently reported in the progression of hepatic diseases. This study aimed to investigate the possible role of ferroptosis and pyroptosis in PM_2.5-induced hepatocyte toxicity in LO2 cells (25, 50, or 100 μg/mL, 24 h) and liver injury in mice (10 mg/kg, intranasal administration, twice a week for 15 times). Our results revealed that PM_2.5 induced a dose-related cytotoxic effect on LO2 cells and mouse liver injuries as well as increased activities of aspartate aminotransferase and alanine aminotransferase. These findings were accompanied by Fe²⁺ accumulation, resulting from iron transport system disruption and ferritinophagy activation. The excess free Fe²⁺ induced reactive oxygen species (ROS) overproduction, glutathione (GSH) depletion, glutathione peroxidase (GPX) activity loss, differential regulation of Nrf2 pathway elements, decreasing expression of the GPX4 protein, increasing expression of <i>PTGS2</i> and <i>ACSL4</i> genes and lipid peroxides, and finally initiation of ferroptosis. Along with tissue inflammation, overexpression of <i>HMGB1</i> and proinflammatory cytokines, hepatocyte pyroptosis as indicated by cellular pyroptotic characteristics, NLRP3 inflammasome activation, and Gasdermin D cleavage were also induced by PM_2.5. The mitigating effects of deferoxamine on the above effects suggested ferroptosis and pyroptosis and the subsequent inflammation responses as potential mechanisms underlying PM_2.5-induced liver toxicity. These results demonstrated that PM_2.5 induced inflammation-associated hepatocyte toxicity and liver injury via the activation of ferroptosis and pyroptosis caused by iron accumulation-triggered oxidative stress. Our study revealed the potential role of different programmed cell death patterns in PM_2.5-induced hepatic toxicity.