FZD7 drives ferroptotic retinal injury in DR through β-catenin-dependent suppression of the DHODH/FSP1 ferroptosis-defense pathway, and inhibition of FZD7 restores endogenous anti-ferroptotic mechanisms and confers retinal protection.
Key Findings
Results
Bioinformatic screening identified FZD7 as one of four hub genes associated with diabetic retinopathy, and FZD7 was significantly upregulated in high glucose-treated ARPE-19 cells.
Integrated bioinformatic analyses were used to identify core DR-associated genes.
Four hub genes total were identified through this screening process.
FZD7 upregulation was validated by RT-qPCR in high glucose (HG)-treated ARPE-19 cells.
FZD7 was selected for further mechanistic investigation based on its upregulation profile.
Results
FZD7 promoted ferroptosis in high glucose-treated ARPE-19 cells through β-catenin-dependent suppression of the ferroptosis-defense proteins DHODH and FSP1.
Gain- and loss-of-function experiments were performed in HG-treated ARPE-19 cells.
FZD7 activation led to suppression of both DHODH and FSP1, which are ferroptosis-defense proteins.
The mechanism was characterized as β-catenin-dependent.
FZD7-mediated ferroptosis was associated with iron accumulation, oxidative stress, lipid peroxidation, and mitochondrial dysfunction.
Results
FZD7 silencing restored DHODH and FSP1 expression, attenuated ferroptotic injury, and preserved mitochondrial integrity in high glucose-treated cells.
Loss-of-function experiments demonstrated that silencing FZD7 reversed suppression of the DHODH/FSP1 axis.
FZD7 knockdown attenuated ferroptotic injury markers including iron accumulation and lipid peroxidation.
Mitochondrial integrity was preserved upon FZD7 silencing.
These findings support a direct causal role of FZD7 in ferroptosis-mediated cellular damage.
Results
Pharmacological inhibition of FZD7 in streptozotocin-induced DR mice alleviated retinal ferroptosis, reduced oxidative damage, and improved retinal ultrastructural abnormalities.
A streptozotocin-induced DR mouse model was used for in vivo validation.
Pharmacological FZD7 inhibition was assessed for effects on retinal ferroptotic injury and pathological changes.
Treatment reduced retinal oxidative damage in vivo.
Retinal ultrastructural abnormalities were improved following FZD7 inhibition.
In vivo results were consistent with in vitro mechanistic findings.
Conclusions
FZD7 is established as a previously unrecognized therapeutic target for diabetic retinopathy through its regulation of the DHODH/FSP1 ferroptosis-defense pathway.
The DHODH/FSP1 axis represents a downstream effector pathway through which FZD7 mediates retinal injury.
The study describes FZD7 as 'a previously unrecognized therapeutic target for diabetic retinopathy.'
Both pharmacological and genetic approaches to FZD7 inhibition conferred retinal protection.
What This Means
This research suggests that a protein called FZD7 plays a previously unknown role in driving a specific type of cell death called ferroptosis in the retinas of people with diabetic retinopathy (DR), a leading cause of blindness in diabetic patients. Ferroptosis is a form of cell death driven by iron accumulation and damage to fats in cell membranes. The researchers found that FZD7 levels are elevated in diabetic retinal conditions, and when FZD7 is active, it suppresses two protective proteins (DHODH and FSP1) that normally help cells defend against ferroptosis — doing so through an intermediate protein called β-catenin. This chain of events leads to iron buildup, oxidative stress, fat damage, and mitochondrial dysfunction in retinal cells.
When the researchers blocked FZD7 — either by silencing the gene in cell experiments or by using a drug in diabetic mice — the protective proteins DHODH and FSP1 were restored, ferroptotic cell death was reduced, and the structural integrity of the retina was better preserved. These findings held up in both laboratory cell models and in living animals with experimentally induced diabetes.
This research suggests that targeting FZD7 could represent a new therapeutic strategy for diabetic retinopathy by reactivating the body's own defenses against a damaging form of cell death. Current treatments for DR focus on other mechanisms, so identifying FZD7 and the DHODH/FSP1 pathway as a druggable axis opens a potentially new avenue for protecting vision in diabetic patients, though further research including human clinical studies would be needed before any clinical application.
Jiang J, Zheng L, Wang L, Li J, Liao J, Su X, et al.. (2026). FZD7 drives retinal ferroptosis in diabetic retinopathy via β-catenin-dependent suppression of the DHODH/FSP1 axis.. Journal of pharmacological sciences. https://doi.org/10.1016/j.jphs.2026.07.006