Systematic review of antifibrotic effects of metformin: Insights from preclinical and clinical studies and potential relevance to oral submucous fibrosis

Fibrosis involves excessive deposition of extracellular matrix, leading to ongoing tissue remodeling and organ failure. Metformin, a common antidiabetic medication, has shown potential antifibrotic effects by affecting AMP-activated protein kinase (AMPK) and transforming growth factor-beta (TGF-β) signaling pathways. This systematic review aimed to synthesize the current evidence on the antifibrotic effects of metformin and to explore its potential translational relevance to oral submucous fibrosis (OSF). The review was conducted in accordance with the PRISMA 2020 guidelines and prospectively registered with PROSPERO (CRD42024531382). A total of 29 studies were included, comprising 3 randomized controlled trials, 1 observational cohort study, 11 in vivo studies, 4 in vitro studies, and 10 combined in vitro/in vivo investigations. The included studies evaluated the effects of metformin on fibrosis-related outcomes across multiple organ systems. No studies directly investigating metformin in OSF were identified; therefore, its potential relevance to OSF was inferred from shared molecular and pathogenic mechanisms underlying fibrogenesis. Metformin demonstrated consistent antifibrotic activity across multiple experimental models, primarily mediated through activation of AMP-activated protein kinase (AMPK), inhibition of TGF-β/ Smad signaling, modulation of mTOR pathways, and attenuation of oxidative stress and inflammatory responses. Emerging experimental evidence, not directly derived from the included clinical studies, also suggests a potential role for metformin in modulating exosome-mediated intercellular signaling involved in fibrogenesis. Despite robust mechanistic and preclinical evidence, clinical data remain limited, with few randomized studies and reliance on indirect fibrosis-related endpoints. Current findings support the potential of metformin as a repurposed antifibrotic agent; however, available human evidence remains limited, and no direct studies have evaluated its efficacy in OSF. Consequently, well-designed prospective studies are needed to validate its antifibrotic effects and to determine its therapeutic applicability to OSF. Overall, metformin is a multifaceted pharmacological candidate with promising translational potential across fibrotic disorders, although direct evidence supporting its role in OSF remains to be established.