γ-Linolenic acid derived from Lactobacillus plantarum MM89 induces ferroptosis in colorectal cancer

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide; however, current treatment options are inadequate, necessitating the exploration of new therapeutic strategies. The microbiota significantly influences the tumor microenvironment, suggesting that probiotics may serve as promising candidates for cancer treatment. We previously identified a novel probiotic, Lactobacillus plantarum MM89 (L. plantarum MM89), which was found to regulate the immune microenvironment. However, its specific role in CRC remained unclear. In this study, we employed an azoxymethane/dextran sodium sulfate-induced carcinogenesis mouse model to evaluate the therapeutic effects of L. plantarum MM89 in vivo. Transcriptome analysis was conducted to elucidate the mechanisms of action of L. plantarum MM89. Ferroptosis induction in tumor cells was assessed through cell viability assays and C11-BODIPY staining. Liquid chromatography/mass spectrometry was used to identify metabolites derived from L. plantarum MM89. MitoTracker and MitoTracker CMXRos staining and ATP content measurements were performed to assess mitochondrial damage. L. plantarum MM89 significantly inhibited tumor growth in vivo and alleviated intestinal inflammation at non-tumor foci. Transcriptome analysis and immunohistochemistry revealed that L. plantarum MM89 enhanced arachidonic acid metabolism. Small molecules present in the L. plantarum MM89 supernatant induced ferroptosis in cancer cells, as indicated by cell viability and C11-BODIPY assays. Furthermore, γ-linolenic acid (γ-LA) derived from L. plantarum MM89 was shown to induce ferroptosis via mitochondrial damage. In conclusion, γ-LA derived from L. plantarum MM89 triggers ferroptosis in tumor cells by inducing mitochondrial damage, highlighting its potential as a novel therapeutic agent for CRC treatment.