To investigate the impact of dietary arsenic exposure on hepatic lipid metabolism and its underlying molecular mechanisms, C57BL/6 mice were chronically fed arsenic-containing chow, and an arsenic-exposed HepG2 cell model was used. Mouse liver structure was examined with transmission electron microscopy, and lipid metabolism indicators in HepG2 cells were analyzed through immunoblotting and assay kits. Results showed a significant reduction in both the number and size of lipid droplets in the livers of the arsenic-exposed group. In vitro experiments revealed decreased expression of Sterol Regulatory Element Binding Protein-1c (SREBP-1c) and Fatty Acid Synthesis (FASN) proteins in HepG2 cells exposed to arsenic concentrations ranging from 10 to 40 μmol/L (SREBP-1c: 0.73, 0.60, 0.54, 0.40; FASN: 0.88, 0.77, 0.75, 0.82). Levels of triglycerides (TG) and total cholesterol (TC) also declined (TG: 0.94, 0.78, 0.78, 0.73; TC: 0.95, 0.73, 0.70, 0.57), indicating arsenic-induced lipid metabolism disruption. Additionally, phosphorylated Extracellular Signal-Regulated Kinase (ERK) expression increased significantly following arsenic exposure (5.72, 23.78, 33.20, 47.17), suggesting ERK pathway activation. Pre-treatment with PD98059, an ERK activation inhibitor, led to increased SREBP-1c and FASN expression in arsenicexposed HepG2 cells (SREBP-1c: 1.2; FASN: 1.3), as well as elevated TG and TC levels (TG: 1.2; TC: 1.2). These findings provide a theoretical basis for the role of ERK signaling in arsenic-induced lipid metabolism disorders in HepG2 cells.