Microbiota metabolite lithocholic acid in cancer: Mechanisms and therapeutic potential

The human gut microbiome is centrally implicated in host disease and health control via the production of a range of bioactive metabolites. Of these, lithocholic acid (LCA), a derivative of microbial metabolism secondary bile acid, has received attention owing to its multifaceted functions in cancer. LCA, a hydrophobic microbiota-derived bile acid, was implicated in carcinogenicity and hepatotoxicity even in the ancient era. In this sense, studies have found a contrasting role of LCA as a tumor promoter or tumor suppressor based on the molecular environment and type of tumor. Antitumor effects of LCA have also been observed in various cancers such as breast, prostate, colon, and neuroblastoma. Interestingly, LCA induces selective apoptosis of cancer cells through intrinsic and extrinsic pathways but without damaging normal cells, and the process is partly caspase-dependent. Mechanistically, LCA induces endoplasmic reticulum (ER) stress response, induces autophagy in certain cancer cell lines, and inhibits mitochondrial function, all contributing to its cytotoxic effect. It also causes oxidative and nitrosative stress through downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1(Keap1) pathway and induction of inducible nitric oxide synthase (iNOS) mediated through TGR5 and Chimeric antigen receptor (CAR) receptor activation. Besides its cytostatic action on itself, LCA was determined to have the capability to modulate the tumor microenvironment through immunomodulation and anti-inflammation, which are behind its therapeutic actions. Via its action on nuclear receptors like the vitamin D receptor (VDR), LCA has been shown to inhibit proteasome activity, create pores in membranes, and alter calcium uptake and epithelial integrity under conditions of oxidative stress. Because of its selective anticancer action, receptor-mediated signal activity, and microbiota origin, LCA is a good cancer drug candidate. This review discusses primarily the molecular processes through which LCA regulates cancer pathogenesis and determines its therapeutic potential based on preclinical and clinical data.