Convergence of ER stress and ferroptosis in diabetic vasculopathy: therapeutic protection by ferrostatin-1

Diabetic vascular complications are driven by endothelial dysfunction and Insulin resistance, their underlying mechanisms remain incompletely understood. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has been implicated in various diseases. However, its role in diabetic vasculopathy is unclear. This study investigated the contribution of Ferroptosis to diabetic endothelial injury and its interplay with oxidative and endoplasmic reticulum (ER) stress. In diabetic db/db mice, the Ferroptosis inhibitor ferrostatin-1 (Fer-1) reduced aortic thickness (-65%), Reactive Oxygen Species production (-87.3%), and improved endothelium-dependent relaxation to acetylcholine (75.6%) and Insulin (73.1%), independent of glycemic control. In human umbilical vein endothelial cells (HUVECs), high glucose induced Ferroptosis, evidenced by mitochondrial shrinkage, downregulation of Glutathione Peroxidase 4/ solute carrier family 7 member 1 (SLC7A11), and lipid peroxidation. Fer-1 co-treatment suppressed these effects, concurrently alleviating oxidative/ER stress and restoring insulin-stimulated phosphoinositide 3-kinase/Akt/endothelial nitric oxide synthase signaling. Mechanistically, quenching oxidative stress with N-acetylcysteine attenuated high glucose-induced ER stress, Ferroptosis, and Insulin resistance. Furthermore, inhibiting ER stress or silencing the pro-apoptotic transcription factor C/EBP homologous protein (CHOP), a known repressor of SLC7A11, attenuated high glucose-induced Ferroptosis and partially restored Insulin signaling. Our findings suggest the presence of a pathway in which high glucose-driven oxidative stress may initiate ER stress, leading to CHOP-mediated suppression of SLC7A11 and subsequent Ferroptosis, thereby contributing to endothelial Insulin resistance. These results raise the possibility that targeting Ferroptosis could represent a promising therapeutic strategy for diabetic vascular complications, possible through mechanisms distinct from glucose-lowering.