Diosgenin presents a novel role in promoting diabetic wound healing: A mechanism involving Sirt6/Nrf2-mediated inhibition of ferroptosis

Delayed wound healing in patients with diabetes is frequently caused by the dysfunction of human umbilical vein endothelial cells (HUVECs). Under high-glucose and high-fat (HGHF) conditions, the microenvironment induces uncontrolled lipid peroxidation and subsequent iron-dependent ferroptosis. Diosgenin (DG), a steroidal saponin extracted from herbs, including wild yam, exhibits diverse pharmacological activities. The present study aimed to investigate the role and underlying mechanism of DG in HGHF-induced ferroptosis and diabetic wound healing. A diabetic wound model was established in mice by intraperitoneal injection of streptozotocin. HUVECs were cultured under HGHF conditions to induce the diabetic microenvironment. C11-BODIPY, FerroOrange probes, and hematoxylin-eosin/Masson staining were used to determine lipid peroxidation, iron ion levels, and histological changes, respectively. Results demonstrated that DG alleviated HGHF-induced ferroptosis, as evidenced by reduced malondialdehyde (MDA), lipid peroxidation, and mitochondrial reactive oxygen species levels, and increased glutathione (GSH) levels. Additionally, DG upregulated the expression of the anti-ferroptotic protein glutathione peroxidase 4 (GPX4), promoted angiogenesis, and accelerated wound healing in diabetic mice. Network pharmacology analysis identified the sirtuin 6/nuclear factor erythroid 2-related factor 2 (Sirt6/Nrf2) pathway as a potential target of DG, a finding validated by mechanistic studies. Silencing Sirt6 in HUVECs negated the protective effect of DG against ferroptosis. In conclusion, DG mitigates ferroptosis and promotes diabetic wound healing, at least partially through activating the Sirt6/Nrf2 pathway. • High glucose and high fatty conditions induce ferroptosis in HUVECs in vitro and promote ferroptosis in diabetic wound tissues in vivo. • Diosgenin inhibits HGHF-induced HUVECs ferroptosis and restores HUVECs functional impairment in vitro. • Diosgenin exerts anti-ferroptotic effects by activating the Sirt6/Nrf2 signaling pathway. • Diosgenin promotes diabetic wound healing in vivo in a Sirt6-dependent manner.