Gut microbiota-derived UDP-GlcNAc co-opts the host O-GlcNAcylation system to fuel breast tumour progression

The gut microbiome is increasingly linked to breast cancer (BC) progression; however, specific microbial metabolites and their direct mechanistic connections to oncogenic signalling remain poorly defined. Here, using multi-omics analyses in treatment-naïve patients with BC, we identified gut microbiota-derived uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) as a circulating oncometabolite associated with therapeutic response. We further showed that Ruminococcus lactaris is a key intestinal commensal capable of de novo UDP-GlcNAc biosynthesis, and that microbial-derived UDP-GlcNAc acts as an independent tumour-promoting metabolite, even though the host hexosamine pathways generate the majority of circulating UDP-GlcNAc pools. Mechanistically, UDP-GlcNAc systemically activates O-GlcNAc transferase (OGT), stabilizing the transcription factor NFIB, and triggers a feed-forward loop that upregulates OGT and the proto-oncogene KIT , thereby driving BC progression. Genetic or pharmacological inhibition of OGT disrupts this signaling axis and suppresses tumour growth, even in the presence of UDP-GlcNAc–producing bacteria. These findings reveal a gut microbiota–metabolite–host signalling circuit, in which a microbial metabolite hijacks a core host post-translational modification pathway to promote BC progression, providing novel opportunities for microbiome-targeted diagnosis and therapy. Gut‑microbiota‑derived UDP‑GlcNAc enters circulation, activates host OGT‑mediated O‑GlcNAcylation to stabilize NFIB. This triggers a feed‑forward loop elevating OGT and proto‑oncogene KIT , driving breast tumor progression. Inhibiting OGT blocks this oncogenic axis even with UDP‑GlcNAc‑producing Ruminococcus lactaris . This reveals a gut‑microbe‑metabolite‑host signaling circuit for breast cancer. Download: Download high-res image (170KB) Download: Download full-size image