Early metabolic rewiring precedes arsenic-induced carcinogenesis in human lung epithelial cells.

Chronic, low-dose inorganic arsenic (iAs) exposure is a major environmental risk factor for lung cancer, yet the early cellular events that link low-dose exposure to carcinogenesis remain poorly understood. Because most people are exposed to iAs at low, chronic doses rather than acutely toxic levels, the metabolic events during this early window are especially relevant to human cancer risk. In this study, we investigated metabolic responses to non-cytotoxic, low-dose iAs exposure (0.5-2.0 µM) in human lung epithelial cells using short (48 h) and long (24-week) exposure models. Integrated transcriptomic and metabolomic analyses revealed that metabolic reprogramming begins within 48 h of exposure, characterized by increased glutathione synthesis, increased glycolysis, and triglyceride accumulation. The early adaptations mirrored the Warburg effect and dynamic lipid remodeling we observed in our chronic model of iAs exposure (0.5 µM). These findings indicate that iAs induces early metabolic rewiring that precedes cell transformation in human lung cells and suggest that low-dose iAs exposure may metabolically prime cells to support later oncogenic events and phenotypes. Metabolic networks underpinning the cellular response to iAs may therefore provide therapeutic targets for preventing or treating iAs-induced lung cancers.