CD36-Mediated Lipid Metabolic Reprogramming in Hepatocellular Carcinoma: Crosstalk With Immunity, Ferroptosis, and Therapeutic Resistance

Hepatocellular carcinoma (HCC) is a leading cause of cancer death and is associated with metabolic dysfunction and chronic liver disease.Lipid metabolic reprogramming is a key hallmark of HCC, and CD36, a fatty acid translocase and scavenger receptor, has emerged as a central regulator of this process.This review investigated the multifaceted roles of CD36 in HCC pathogenesis.CD36 facilitates long-chain fatty acid uptake and affects oncogenic signaling and the tumor immune microenvironment.CD36-mediated lipid accumulation promotes cytotoxic T-cell function and macrophage M2 polarization and drives immune evasion.Likewise, CD36 modulates ferroptosis sensitivity by influencing polyunsaturated fatty acid-induced lipid peroxidation and redox balance.Through metabolic plasticity and oxidative stress adaptation, CD36 also contributes to resistance to chemotherapy, targeted therapies, and immunotherapy.In conclusion, CD36 serves as a critical multifunctional regulator linking lipid metabolism, ferroptosis, immunomodulation, and therapy resistance in HCC, positioning it as a promising therapeutic target for improving clinical outcomes.However, clinical translation remains challenging due to the broad tissue expression of CD36 and the lack of large-scale clinical validation.Hence, future research should focus on clinical validation of CD36, mechanistic elucidation, selective inhibitor development, combination therapy evaluation, and multi-omics-guided personalized HCC treatment.