The Role of Ferroptosis in Diabetes Pathogenesis: Therapeutic Implications of Hydrogen Sulfide and Its Reactive Metabolites

Abstract

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, emerged as an important contributor to the pathogenesis of diabetes and its complications. Impaired glucose and iron metabolism, and increased oxidative stress, predispose cells—particularly pancreatic β-cells and vascular tissues—to ferroptotic cell death, contributing to β-cell dysfunction, insulin resistance, and the progression of diabetic complications. Hydrogen sulfide (H<inf>2</inf>S), an important gasotransmitter, plays a pivotal role in regulating various pathophysiological processes by interfering with key cellular signaling pathways, including those related to cell death. In the context of ferroptosis, H<inf>2</inf>S exerts protective effects by activating the nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4/glutathione (Nrf2/GPX4/GSH) axis, enhancing cellular antioxidative defenses and inhibiting lipid peroxidation. Furthermore, H<inf>2</inf>S modulates key regulators of iron homeostasis and lipid metabolism, including hepcidin, ferritin, and the cystine/glutamate antiporter system (xCT) antiporter, further attenuating ferroptosis. Exogenous administration of H<inf>2</inf>S can reverse ferroptosis-induced cellular injury in several pathological settings and improve metabolic outcomes in diabetic models. These findings suggest that targeting H<inf>2</inf>S signaling is a promising therapeutic strategy to inhibit ferroptosis and mitigate diabetes-related organ dysfunction. This review summarizes current insights into the molecular interplay between H<inf>2</inf>S and diabetes-related signaling pathways, primarily ferroptosis, emphasizing the antiferroptotic therapeutic potential of H<inf>2</inf>S-based interventions for the prevention and treatment of diabetic complications.