Abstract: Objective: Obesity was a growing global health concern that was often accompanied by disorders of lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) was the most prevalent manifestation of such lipid metabolic dysregulation. 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: The results demonstrated that 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: In summary, 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.