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The development of novel therapeutic strategies should prioritize targeting the fundamental pathophysiological mechanisms underlying these diseases, including inflammation, cellular proliferation, and gut microbiota dysregulation. Metformin, a first\u2010line antidiabetic agent, exhibits pleiotropic pharmacological properties beyond its glucose\u2010lowering effects, such as anti\u2010inflammatory, antiproliferative, and microbiota\u2010modulating activities. These multifaceted mechanisms position metformin as a promising therapeutic candidate for a spectrum of disorders, from IBS to liver disorders. This review synthesizes preclinical and clinical evidence supporting the therapeutic potential of metformin across GI pathologies\u2014such as\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Helicobacter pylori<\/jats:italic>\n                    <\/jats:styled-content>\n                    infection, inflammatory bowel disease, colorectal cancer, and hepatocellular carcinoma\u2014while elucidating its molecular mechanisms, such as AMPK\/mTOR modulation, NF\u2010\u03baB inhibition, and gut barrier stabilization. We critically evaluate combination therapies, ongoing clinical trials, and challenges, including lactic acidosis risk and GI intolerance to position metformin as a repurposed agent for GI disease management.\n                  <\/jats:p>","DOI":"10.1002\/prp2.70257","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T04:44:06Z","timestamp":1776746646000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Metformin as a Multifaceted Therapeutic Agent for Gastrointestinal Diseases: Mechanisms, Clinical Efficacy, and Future Directions"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9227-3473","authenticated-orcid":false,"given":"Sayedeh Azimeh","family":"Hosseini","sequence":"first","affiliation":[{"name":"Department of Medical Biotechnology, School of Advanced Technology Shahrekord University of Medical Sciences  Shahrekord Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Valadbeigi","sequence":"additional","affiliation":[{"name":"Clinical Microbiology Research Center Ilam University of Medical Sciences  Ilam Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5394-5660","authenticated-orcid":false,"given":"Seyedeh Mahdieh","family":"Khoshnazar","sequence":"additional","affiliation":[{"name":"Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences Kerman University of Medical Sciences  Kerman Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5143-3178","authenticated-orcid":false,"given":"Saeed","family":"Khoshnood","sequence":"additional","affiliation":[{"name":"Clinical Microbiology Research Center Ilam University of Medical Sciences  Ilam Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3764-2168","authenticated-orcid":false,"given":"Shahab","family":"Falahi","sequence":"additional","affiliation":[{"name":"Zoonotic Diseases Research Center Ilam University of Medical Sciences  Ilam Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9547-3211","authenticated-orcid":false,"given":"Delsuz","family":"Rezaee","sequence":"additional","affiliation":[{"name":"Department of Genetics and Molecular Medicine, School of Allied Medical Sciences Ilam University of Medical Sciences  Ilam Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Hematian","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine Ilam University of Medical Sciences  Ilam Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3387-9379","authenticated-orcid":false,"given":"Mohammad Hossein","family":"Haddadi","sequence":"additional","affiliation":[{"name":"Clinical Microbiology Research Center Ilam University of Medical Sciences  Ilam Iran"},{"name":"Student Research Committee Ilam University of Medical Sciences  Ilam Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"e_1_2_12_2_1","first-page":"17","article-title":"The Role of Telemedicine and e\u2010Health in the Management of Inflammatory Bowel Disease: Improving Patient Outcomes","volume":"3","author":"Ghazi L. 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