FZD7 drives retinal ferroptosis in diabetic retinopathy via β-catenin-dependent suppression of the DHODH/FSP1 axis.

Purpose

To investigate the role of Frizzled-7 (FZD7) in diabetic retinopathy (DR) and elucidate the molecular mechanism by which FZD7 regulates ferroptosis during disease progression.

Methods

Core DR-associated genes were identified through integrated bioinformatic analyses and validated by RT-qPCR. Gain- and loss-of-function experiments were performed in high glucose (HG)-treated ARPE-19 cells to investigate the role of the β-catenin/DHODH-FSP1 pathway in FZD7-mediated ferroptosis. In vivo, a streptozotocin-induced DR mouse model was used to assess the effects of pharmacological FZD7 inhibition on retinal ferroptotic injury and pathological changes.

Results

Bioinformatic screening identified four hub genes associated with DR, among which FZD7 was significantly upregulated and further validated in HG-treated ARPE-19 cells. Mechanistically, FZD7 promoted ferroptosis through β-catenin-dependent suppression of the ferroptosis-defense proteins DHODH and FSP1, leading to iron accumulation, oxidative stress, lipid peroxidation, and mitochondrial dysfunction. Conversely, FZD7 silencing restored DHODH and FSP1 expression, attenuated ferroptotic injury, and preserved mitochondrial integrity. Consistent with these findings, pharmacological inhibition of FZD7 in DR mice alleviated retinal ferroptosis, reduced oxidative damage, and improved retinal ultrastructural abnormalities.

Conclusions

FZD7 drives ferroptotic retinal injury in DR through β-catenin-dependent suppression of the DHODH/FSP1 ferroptosis-defense pathway. Inhibition of FZD7 restores endogenous anti-ferroptotic mechanisms and confers retinal protection, establishing FZD7 as a previously unrecognized therapeutic target for diabetic retinopathy.