LCA, a bacterial metabolite, induces ferroptosis and senescence in triple-negative breast cancer.

Lithocholic Acid (LCA) is a secondary bile acid generated through the microbial metabolism of primary bile acids in the gut. In recent years, it has been found to have potential anti-tumor effects. Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. Chemotherapy remains the primary treatment, but it has significant side effects and often leads to drug resistance. Therefore, exploring new treatment strategies is of great importance. This research seeks to elucidate the mechanism of LCA in TNBC and establish a theoretical foundation for its clinical use. Through cell proliferation assays, iron metabolism detection, oxidative stress analysis, ferroptosis marker detection, and autophagy-related experiments, we systematically investigated the effects of LCA on TNBC cells. The findings indicated that LCA effectively suppressed TNBC cell proliferation and triggered mitochondrial iron overload and oxidative stress, resulting in ferroptosis via ferritinophagy. Molecular mechanism studies revealed that after LCA treatment, the expression of ferroptosis-related markers GPX4 and FTH was downregulated, while NCOA4 expression was upregulated. Autophagy inhibitors or AMPK inhibitors significantly reversed LCA-induced ferroptosis, indicating that LCA induces ferroptosis by promoting ferritinophagy and releasing iron ions. This study elucidates the molecular mechanism by which LCA induces ferroptosis in TNBC cells via regulation of iron metabolism, oxidative stress, and autophagy. It provides crucial experimental evidence and theoretical support for LCA as a potential anti-breast cancer drug, offering novel insights and targets for TNBC treatment.

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