Microbial metabolite 5-formamidoimidazole-4-carboxamide ribotide targets METTL1 to inhibit m7G modification of BRCA1 mRNA to inhibit high-grade serous ovarian cancer.

BACKGROUND: This study explored the impact of vaginal microbes, metabolites, and METTL1-mediated m7G modification of BRCA1 mRNA on High-Grade Serous Ovarian Cancer (HGSOC). METHODS: METTL1 and BRCA1 expression levels were assessed via bioinformatics, Western blotting, and RT-qPCR. Their interaction was studied using RNA co-immunoprecipitation and RNA pull-down assays. The functions and mechanisms of METTL1 and BRCA1 in HGSOC were investigated through CCK-8 assays, flow cytometry, transwell migration assays, and nude mouse xenograft models. We analyzed vaginal microbial and metabolite differences in HGSOC patients with varying BRCA1 expression using 16 S rRNA sequencing and liquid chromatography. Associations were evaluated with Spearman correlation and heat maps, while molecular docking assessed key metabolite binding to METTL1. The roles and interactions of selected metabolites with METTL1/BRCA1 in HGSOC were validated through in vivo and in vitro experiments. RESULTS: In HGSOC, both METTL1 and BRCA1 were up-regulated. METTL1 enhanced BRCA1 expression via m7G modification, boosting cell proliferation and tumor growth. Elevated BRCA1 levels were associated with changes in vaginal microbiota, particularly increased Lactobacillus, and alterations in metabolic pathways. Correlation analysis indicated that Lactobacillus was significantly negatively correlated with 5-formamidoimidazole-4-carboxamide ribotide, inosine, cobalt-precorrin-7, and uridine, but positively correlated with L-lysine. The strongest correlation was with 5-formamidoimidazole-4-carboxamide ribotide. Molecular docking showed that this compound binds strongly to METTL1. Functional tests demonstrated that it inhibits HGSOC cell proliferation and tumor growth by disrupting METTL1-mediated m7G modification of BRCA1. Overexpression of METTL1 or BRCA1 negated its anti-tumor effects. CONCLUSION: The vaginal microbial metabolite 5-formamidoimidazole-4-carboxamide ribotide reduces BRCA1 expression and slows HGSOC progression by modifying BRCA1 m7G through METTL1, suggesting its potential as an HGSOC treatment.