FZD7 Inhibitor SRI Attenuates High Glucose-Induced Retinal Pigment Epithelial Cell Injury Accompanied by Ferroptosis-Associated Changes via Suppression of the Wnt/β-Catenin Pathway.

This study investigated the protective effects of the Frizzled-7 (FZD7) inhibitor SRI against high glucose-induced injury in human retinal pigment epithelial (ARPE-19) cells. It also explored the underlying mechanism, focusing on whether SRI attenuates ferroptosis and apoptosis by inhibiting the Wnt/β-catenin signalling pathway. ARPE-19 cells were exposed to high glucose (25 mM) and treated with a non-cytotoxic concentration of SRI (2 μmol/L), as determined by a CCK-8 assay. Wnt/β-catenin signalling was evaluated by measuring β-catenin expression and phosphorylation. The expression of GPX4, DHODH, and FSP1, together with intracellular Fe²⁺, ROS, and MDA levels, was assessed to evaluate ferroptosis and oxidative stress. Apoptosis was analysed by examining Bax and Bcl-2 expression, whereas mitochondrial ultrastructure was evaluated using quantitative transmission electron microscopy. Under hyperglycaemic conditions, SRI suppressed Wnt/β-catenin signalling by reducing β-catenin expression and promoting its phosphorylation. SRI activated a GPX4-independent ferroptosis defence pathway, evidenced by increased DHODH and FSP1 expression without affecting GPX4 levels. Furthermore, SRI reduced intracellular Fe²⁺, ROS and MDA accumulation, downregulated Bax, upregulated Bcl-2 and improved mitochondrial morphology with partial restoration of cristae integrity. Collectively, these findings demonstrate that SRI alleviates high glucose-induced oxidative stress, ferroptosis, apoptosis and mitochondrial damage. SRI protects ARPE-19 cells from high glucose-induced injury by reducing ferroptosis-associated oxidative stress, apoptosis and mitochondrial dysfunction. These protective effects are mediated, at least in part, through inhibition of Wnt/β-catenin signalling and activation of a DHODH/FSP1-dependent but GPX4-independent ferroptosis defence pathway. These findings suggest that FZD7 represents a promising therapeutic target for diabetic retinopathy.