{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:40Z","timestamp":1787027860392,"version":"build-2736575974"},"reference-count":173,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172763"],"award-info":[{"award-number":["82172763"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82172763"],"award-info":[{"award-number":["82172763"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Metformin, widely prescribed for type 2 diabetes mellitus (T2D), has emerged as a systemic immunomodulator with effects that extend far beyond glycemic control. Recent advances in immunometabolism reveal that metformin modulates innate immune responses through coordinated cellular metabolic reprogramming and epigenetic modification, which collectively modulate the functional phenotype of innate immune cells. This narrative review summarizes current evidence regarding the immunomodulatory effects of metformin on the innate immune system, with a focus on immunometabolism and epigenetic regulation. It explores how metformin modulates innate immunity by altering cellular energy sensing, mitochondrial function, and nutrient utilization. Such metabolic changes and alterations further reshape chromatin structure and architecture, as well as transcriptional profiles and programs. Through the regulation of glycolysis, fatty acid oxidation, and histone modification landscapes, metformin regulates the phenotypes of innate immune cells, which can be pro-inflammatory, tolerogenic, or homeostatic. This conceptual framework presents a new understanding of metformin. As well as acting as an anti-inflammatory agent, it may regulate immune memory.<\/jats:p>","DOI":"10.3390\/cimb48060642","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T07:57:24Z","timestamp":1782287844000},"page":"642","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Metformin as an Innate Immune Modulator: Metabolic and Epigenetic Reprogramming of Innate Immune Cells and Therapeutic Implications"],"prefix":"10.3390","volume":"48","author":[{"given":"Yunfeng","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0663-6988","authenticated-orcid":false,"given":"Sheng","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.chom.2011.04.006","article-title":"Trained Immunity: A Memory for Innate Host Defense","volume":"9","author":"Netea","year":"2011","journal-title":"Cell Host Microbe"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1093\/infdis\/jir240","article-title":"Randomized Trial of BCG Vaccination at Birth to Low-Birth-Weight Children: Beneficial Nonspecific Effects in the Neonatal Period?","volume":"204","author":"Aaby","year":"2011","journal-title":"J. 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