Targeting Caveolin-1 Alleviated Diabetic Retinopathy Injury through Protecting Müller Cells from Ferroptosis via the xCT/GPX4 Signaling Pathway

Abstract Diabetic retinopathy (DR) is a global blinding eye disease, and its early pathological features are closely associated with retinal Müller cell dysfunction. Caveolin-1 (Cav-1) is a protein widely expressed in mammalian tissues and participates in regulating Müller cell function; however, its role in DR remains unclear. This study provides evidence that Cav-1 alleviates DR pathology and elucidates the underlying mechanisms. Müller cells were treated with high glucose, and diabetes was induced in Sprague–Dawley rats by streptozotocin injection. Cav-1 expression levels were modulated using the Caveolin-1 scaffolding domain peptide CSD, as well as Cav-1 knockdown or overexpression. The results showed that under high glucose stress, inhibition of Cav-1 expression significantly reduced intracellular ACSL4 protein levels, ROS levels, MDA and Fe2+ concentrations, while increasing GSH content and the protein expression of SLC7A11 and GPX4. Notably, treatment with the GPX4 inhibitor RSL3 abolished this protective effect, confirming the involvement of the xCT/GPX4 pathway in Cav-1-mediated protection. In vivo, CSD treatment exerted protective effects as early as week 8. Electron microscopy revealed that, compared with diabetic rats, CSD treatment ameliorated mitochondrial edema and restored mitochondrial cristae structure. Furthermore, immunofluorescence staining showed spatial consistency between Cav-1 protein expression and Müller cell localization. These findings indicate that targeting Cav-1 alleviates oxidative stress, reduces ferroptosis, and ameliorates early-stage DR injury by activating the xCT/GPX4 signaling pathway, suggesting that Cav-1 targeting may represent a novel therapeutic strategy for DR.