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This study repurposes metformin as a dual-function agent that simultaneously targets bacterial virulence and host inflammation. Epidemiological surveillance identified phylogroup B1 as the most prevalent (52.5%) and resistant\n                    <jats:italic>E. coli<\/jats:italic>\n                    lineage. Against a representative B1 strain, metformin potently inhibited and dispersed bacterial biofilms, and synergized with conventional \u03b2-lactam antibiotics. Bacterial transcriptomics revealed metformin downregulated genes critical for membrane integrity and metabolism. In parallel, metformin attenuated the inflammatory response in bovine mammary epithelial cells and in murine and ovine mastitis models. In vivo, it significantly reduced bacterial colonization in mammary tissue and suppressed key pro-inflammatory cytokines. Mechanistically, metformin activated the AMPK\/SIRT1 axis, leading to deacetylation of NF-\u03baB p65. In the ruminant model, this culminated in epigenetic regulation, with increased chromatin compaction at promoters of inflammatory genes, and a significant inverse correlation (r\u2009=\u2009-0.77) between NF-\u03baB binding and chromatin accessibility. Collectively, metformin combats resistant\n                    <jats:italic>E. coli<\/jats:italic>\n                    mastitis through a dual mechanism: disrupting biofilm-dependent bacterial persistence and reprogramming host immunometabolism via AMPK\/SIRT1-mediated epigenetic regulation. These findings provide a compelling non-antibiotic strategy for overcoming antimicrobial resistance.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014012","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T18:43:11Z","timestamp":1772822591000},"page":"e1014012","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Repurposing metformin as a dual-function agent to combat E. coli-induced mastitis: Mechanistic insights into biofilm dispersion and AMPK\/SIRT1-mediated NF-\u03baB 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