SLC7A11-mediated disulfidptosis underlies the pathogenesis of proliferative diabetic retinopathy.

Abstract

Background: We investigated the role of disulfidptosis, a recently identified form of cell death, in the pathogenesis of proliferative diabetic retinopathy (PDR) and explore the function of the cystine/glutamate antiporter, SLC7A11, as a key mediator and potential therapeutic target.

Methods: Bioinformatic analysis was used to screen disulfidptosis-related genes from public RNA sequencing datasets, which were subsequently validated in PDR fibrovascular membranes (FVMs) and vitreous humor via immunofluorescence and western blotting analysis. Human retinal microvascular endothelial cells (HRMECs) were cultured in normal or high-glucose media, and SLC7A11 expression modulated using small interfering RNA or lentiviral overexpression. Angiogenesis was assessed via proliferation, migration, and tube formation assays. Disulfidptosis was induced via acute glucose deprivation in high-glucose-adapted HRMECs and biochemically evaluated. A streptozotocin-induced diabetic mouse model was utilized to assess SLC7A11 expression in vivo, and therapeutic efficacy was tested through weekly intravitreal lavage with glucose-free versus glucose-replete solutions.

Results: Disulfidptosis-related genes, particularly SLC7A11, were significantly upregulated in PDR FVMs, predominantly localizing to the vascular endothelium. In vitro, high-glucose conditions induced SLC7A11 and vascular endothelial growth factor A expression in HRMECs, thereby promoting proliferation, migration, and tube formation. SLC7A11 knockdown abrogated these pro-angiogenic effects, whereas overexpression exacerbated them. Critically, high-glucose-adapted cells developed a profound dependency on glucose; subsequent acute glucose deprivation triggered rapid cell death, exhibiting classic disulfidptosis features (F-actin collapse), a process that could not be rescued by ferroptosis inhibitors. In the diabetic mouse model, SLC7A11 expression was similarly upregulated in the pathological retinal vasculature. Therapeutic vitreous lavage with a glucose-free solution significantly attenuated the progression of these pathological neovessels.

Conclusions: Our results revealed a novel SLC7A11-mediated metabolic vulnerability in PDR. We demonstrated that exploiting this glucose dependency via localized deprivation induces disulfidptosis-like features in neovascular cells, representing a new therapeutic strategy for PDR.