The Ogt-Nlrp3-Gsdmd Axis Drives Lens Epithelial Cell Pyroptosis In Diabetic Cataract

To investigate the role of the O-GlcNAc transferase (OGT)-NLRP3 inflammasome-gasdermin D (GSDMD)-mediated pyroptosis pathway in the pathogenesis of diabetic cataract (DC).

Diabetic cataract is a common complication of diabetes. Due to the metabolic disorder of the lens caused by high blood sugar, protein glycosylation and oxidative stress damage, it eventually leads to lens opacity and vision impairment.

 Diabetes mellitus was induced in 6-8-week-old male Sprague-Dawley rats via intraperitoneal injection of streptozotocin (STZ, 60 mg/kg). Random blood glucose, lens opacity scores, and histopathological changes via hematoxylin-eosin (HE) staining were examined at 8 and 12 weeks. Expression levels of NFAT2, OGT, NLRP3, caspase-1, and GSDMD in lens tissues were determined by real-time PCR and Western blot.

 Diabetic rats maintained blood glucose levels ≥16.7 mmol/L. Compared with the control group, the model group exhibited progressive elevation of lens opacity scores (reaching 3.6±0.2 grade at 12 weeks, p<0.001). HE staining revealed disorganized lens epithelial cells (LECs), vacuolation, and liquefaction of cortical fiber cells. At the molecular level, NLRP3 protein expression was significantly upregulated, caspase-1 activation and cleavage were increased, and GSDMD-N terminal fragment accumulation was observed. Moreover, OGT and NFAT2 expression exhibited time-dependent elevations (NFAT2 mRNA upregulated by ~6-fold and OGT by ~4-fold at 12 weeks, p<0.001).

Chronic hyperglycemia promotes DC development by activating the OGT-NLRP3-GSDMD pyroptotic pathway, leading to LECs injury. This provides a novel molecular target for anti-inflammatory therapy in DC.