Oral Exposure of Arsenic-Contaminated Soils Triggers Hepatic Ferroptosis via Iron Dysregulation and Glutathione Metabolism Disruption: From Bioavailability to Mechanisms

Unintentional ingestion of arsenic (As) from contaminated mining and smelting soil poses significant health risks, particularly to liver function. While As-induced hepatotoxicity is documented, the mechanisms linking oral exposure to liver damage remain poorly understood. In this study, we characterized As bioaccessibility through in vitro Solubility Bioaccessibility Research Consortium assays and determined its relative bioavailability using a mouse model. Following 10-day oral exposure, bioaccessibility assays revealed significant variation in As availability. Bioavailable arsenic accumulated in liver tissue, leading to iron overload and oxidative stress. Integrative transcriptomic and metabolomic analyses revealed ferroptosis as the primary mechanism of As-induced programmed cell death in hepatocytes. We discovered that oral As exposure triggers a cascade leading to ferroptosis: disruption of iron homeostasis, impairment of glutathione metabolism, and excessive lipid peroxide production. Mechanistically, As exposure decreased cysteine and glutathione levels while promoting iron accumulation, creating preferred conditions for ferroptotic cell death. These changes were accompanied by altered expression of key iron regulatory genes and disrupted antioxidant pathways, affecting glutathione-dependent defense systems. Our findings establish ferroptosis as critical in As-induced hepatotoxicity and provide insights for risk assessment and therapeutic development. This work advances our understanding of As toxicity mechanisms and offers potential targets for intervention strategies.