PCBP1 modulates cellular iron homeostasis via targeting HIF-1α/HO-1 pathway and alleviates high-glucose-induced ferroptosis in HRMECs.

Diabetic retinopathy (DR), is established as one of the leading causes of blindness in adults. Recently, evidence has emerged indicating that the iron and ferroptosis may be involved in the retinal microangiopathy inherent to DR. Here, we first identified significant differential expression of ferroptosis-related genes (FRGs) in a genetic screening of patients with PDR. Through functional analysis and protein validation of the FRGs, we hypothesized that Poly(rC)-Binding Protein 1 (PCBP1), HIF-1α and HO-1, may be associated with the ferroptosis in the DR. Then, high-glucose (HG)-stimulated human retinal microvascular endothelial cells (HRMECs) were used to investigate their specific mechanisms. In order to confirm the induction of ferroptosis by HG, ferroptosis inducers and inhibitors were added to the model. Under HG conditions, lipid peroxidation, ROS, ferrous iron accumulation, MDA, and ferroptosis markers increased, whereas cellular viability and GSH/GSSG levels decreased, all in a time-dependent manner. Furthermore, the downregulation of PCBP1 activated the HIF-1α/HO-1 pathway, which was characterised by an aberrant expression of iron regulatory proteins and an imbalance in iron homeostasis. PCBP1 overexpression or the HO-1 inhibitor, ZnPP, could partly alleviate iron overload and mitigate all the above ferroptotic phenotypes. Our results broadens the understanding of the relationship between DR and ferroptosis and provides a new therapeutic target for the treatment of DR by maintaining endothelial iron homeostasis and thereby inhibiting ferroptosis.