Elabela promotes the retinal angiogenesis by inhibiting ferroptosis during the vaso‐obliteration phase in mouse oxygen‐induced retinopathy model

Abstract Retinopathy of prematurity (ROP) is a leading cause of childhood blindness associated with retinal vaso‐obliteration in phase 1 and pathological neovascularization (NV) in phase 2; however, effective and safe treatments for ROP definitive treatment are yet to be determined. Anti‐vascular endothelial growth factor (VEGF) therapy mainly focuses on reducing abnormal NV in phase 2 but with high risks of late recurrence and systemic side effects. Previous studies have established that the severity of vaso‐obliteration in phase 1 largely influences subsequent stages, suggesting that prevention of vessels loss may be a potential therapeutic target for ROP. Herein, the therapeutic potential and safety of early Elabela intervention treatment in treating phase 1 ROP and the possible underlying mechanisms were investigated using an oxygen‐induced retinopathy (OIR) mouse model. It was observed that intraperitoneal injection of Elabela remarkably reduced the avascular retinal area and increased the vascular density in phase 1 of OIR mice. Further investigation revealed that mitochondrion‐dependent ferroptosis was involved in oxidative stress‐mediated vascular protection loss in phase 1 OIR. Furthermore, we demonstrated that Elabela could rescue mitochondria‐dependent ferroptosis via mediating the xCT/GPX4 axis. Collectively, our study revealed that ferroptosis may play a significant role in early ROP, while Elabela may be a safe and promising strategy for the early intervention of ROP.