Abstract: Objective: This study aimed to investigete the potential and molecular mechanisms of Oudemansiella raphanipies extract (ORE) in ameliorating lipid metabolism dysregulation. Methods: A lipid accumulation model was established in HepG2 cells using free fatty acids (FFA) to investigate the effects of ORE on obesity-associated hepatic steatosis. Oil red O staining were used to detect lipid deposition within cells. Relevant cellular parameters were measured using biochemical assay kits. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were employed to elucidate the molecular mechanisms underlying ORE's improvement of lipid metabolism. Results: ORE effectively reduced lipid accumulation in HepG2 cells. It significantly downregulated the expression of adipogenesis-related genes and proteins, including C/EBPα, PPARγ, SREBP-1c, and FAS. Additionally, ORE significantly reduced reactive oxygen species (ROS) and malondialdehyde (MDA) levels while enhanced the activity of superoxide dismutase (SOD) and catalase (CAT). Conclusion: ORE can improve the lipid metabolism level of lipid-deposited HepG2 cells. The underlying mechanism may be achieved by downregulating C/EBPα and PPAR-γ to further inhibit the SREBP-1c/FAS synthesis pathway. Concurrently, ORE alleviates oxidative stress in HepG2 cells, potentially through reducing ROS、MDA, enhancing SOD and CAT activities, thereby modulating the cellular redox system.