Mechanism of protective effect of curcumin on diabetic retinopathy by attenuating STAT3/GSDME signaling pathway-mediated cellular pyroptosis

Objective: Diabetic retinopathy (DR) is a major microvascular complication of diabetes. This study aimed to elucidate the protective effects of curcumin, a bioactive dietary compound derived from turmeric, and its underlying mechanisms in DR.Materials and Methods: Network pharmacology was used to identify potential curcumin targets and DR-associated genes. Molecular docking was performed to evaluate binding affinities with core targets. Experimental validation was conducted using a streptozotocin-induced DR rat model and high-glucose–treated human retinal microvascular endothelial cells (HRMECs). Retinal pathology was assessed using hematoxylin–eosin (HE) staining, immunohistochemistry, and transmission electron microscopy. The expression levels of cleaved caspase-3, IL-1β, STAT3, DNMT1, GSDME-N, and GSDME were analyzed by western blotting, quantitative PCR (qPCR), immunofluorescence, and co-immunoprecipitation. Apoptosis and intracellular reactive oxygen species (ROS) levels were measured. Results: Network analysis identified five core targets (CCND1, SERPINE1, HSP90AA1, DNMT1, and B2M). EFunctional enrichment analysis indicated significant involvement in DNA methylation, chromatin modification, neutrophil degranulation, and interleukin signaling pathways. In vivo, early curcumin intervention alleviated retinal damage and vascular abnormalities in DR rats. In vitro, curcumin reduced ROS production and apoptosis. Curcumin suppressed the expression of cleaved caspase-3, IL-1β, STAT3, DNMT1, GSDME-N, and GSDME. Mechanistically, STAT3 positively regulated DNMT1, which in turn modulated GSDME expression.Co-immunoprecipitation further confirmed a direct interaction between STAT3 and DNMT1. Conclusion: Curcumin protects against DR by inhibiting the STAT3/DNMT1/GSDME signaling axis, thereby reducing pyroptosis and preserving retinal integrity. These findings support its traditional use and highlight its potential as a multitarget therapeutic strategy for early-stage DR.