Metformin targets RRM2/GSS/GPX4 axis to induce fibroblast ferroptosis: A foreground strategy against hypertrophic scarring

Metformin (Met), a first-line therapeutic agent for type 2 diabetes, has been widely recognized for its antifibrotic properties in various pathological conditions. However, its effects on hypertrophic scars (HS) and the underlying mechanisms remain insufficiently explored. The present study aimed to elucidate the role of metformin in HS and to investigate its associated molecular mechanisms. Both in vitro and in vivo experiments demonstrated that metformin markedly inhibited the proliferation, migration, and collagen deposition of hypertrophic scar fibroblasts (HSFs), and alleviated HS formation in a rabbit ear model. Mechanistic investigations further revealed that these effects were closely associated with the downregulation of ribonucleotide reductase regulatory subunit M2 (RRM2). Notably, reduced RRM2 expression suppressed the production of glutathione synthetase (GSS), thereby impairing glutathione (GSH) synthesis. This, in turn, indirectly downregulated glutathione peroxidase 4 (GPX4), leading to the intracellular accumulation of peroxides and triggering ferroptosis in vivo and in vitro. Collectively, these findings suggest that metformin may attenuate HS fibrosis by inducing HSFs ferroptosis through the RRM2/GSS/GPX4 signaling axis. This study not only expands the potential clinical application of metformin in the treatment of skin fibrosis but also provides a theoretical foundation for the development of novel anti-scar therapeutics. Figure 9 Schematic diagram of the molecular mechanism of metformin in the treatment of HS.Metformin inhibits collagen deposition in HS and suppresses the RRM2/GSS/GPX4 pathway by downregulating RRM2, thereby inducing ferroptosis in HSFs and ultimately alleviating skin fibrosis. • Metformin induces ferroptosis in hypertrophic scar fibroblasts through RRM2/GSS/GPX4 axis. • Metformin significantly reduces collagen deposition and α-SMA expression in multiple animal models. • The study provides new insights into metformin’s potential as a therapeutic strategy for hypertrophic scarring. • RRM2 overexpression reverses metformin’s anti-scarring effects in the rabbit ear model.