Targeting Fatty Acid Synthase to Halt Tumor Progression and Enhance Radiosensitivity in Breast Cancer Cells

Abstract Purpose Breast cancer, the most prevalent cancer among women, is closely linked to abnormal glucose and lipid metabolism, leading to radioresistance by upregulating survival-signaling pathways. Overexpression of fatty acid synthase (FASN), a key enzyme in lipogenesis, results in excessive lipid synthesis in breast cancer. This study evaluated whether FASN inhibition enhanced the radiosensitivity of breast cancer cells and inhibited their progression, potentially uncovering mechanisms for new therapeutic strategies. Methods MCF-7 breast cancer cells were treated with the FASN inhibitors orlistat and TVB-3166, and cytotoxicity was assessed using the MTT assay. Protein expression changes, migratory ability, and responses to radiotherapy were analyzed by the Western blotting, Transwell, and MTT assays, respectively. To confirm FASN dependence, MCF-7 cells were infected with shFASN lentivirus to verify the specificity of the observed effects to FASN inhibition. Results Both orlistat and TVB-3166 treatments induced significant cell death. Reduced FASN, HKII, pERK, and pAKT expression levels, along with an increased BAX/p-BCL2 ratio, indicate that FASN inhibition disrupted cell proliferation and promoted apoptosis by altering tumor metabolism. Furthermore, decreased MMP9 expression correlated with reduced cell migration after FASN inhibition. Importantly, FASN inhibition significantly and dose-dependently enhanced the radiosensitivity of MCF-7 cells. These findings were validated using shFASN lentivirus, confirming that the observed effects were FASN-dependent. Conclusion FASN inhibition limited survival and migration and enhanced radiosensitivity in MCF-7 cells. These findings indicate the potential efficacy of FASN inhibitors as standalone therapies or as adjuncts to radiotherapy for breast cancer.