Inhibition of cGAS-STING signaling and NLRP3 inflammasome-mediated pyroptosis reduces lens opacity and inflammation in high glucose-induced cataract

Abstract Diabetic cataract (DC) is a major cause of visual impairment among diabetic individuals, involving significant inflammatory injury to lens epithelial cells (LECs). However, mechanisms linking high glucose (HG) conditions to inflammatory cell death in LECs remain incompletely understood. This study investigated the role of cytosolic DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling in promoting NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis-associated injury in DC. We found that cGAS, STING, NLRP3, caspase-1, and gasdermin D (GSDMD) were significantly upregulated in LECs from human DC anterior lens capsules. In vitro, HG exposure induced cytosolic DNA accumulation, mitochondrial DNA release and cGAS-STING signaling activation in human LECs, accompanied by upregulation of NLRP3 inflammasome, ASC, cleavage of caspase-1 and GSDMD, lactate dehydrogenase (LDH) release, and elevated secretion of interleukin-1β (IL-1β) and IL-18. Knocking down NLRP3 with small interfering RNA (siRNA) effectively attenuated pyroptosis-associated responses of LECs under HG, with decrease of ASC, cleaved caspase-1, cleaved GSDMD, LDH release, and secretion of IL-1β and IL-18. Furthermore, knockdown of cGAS or STING suppressed activation of the NLRP3-caspase-1-GSDMD axis, suggesting cGAS-STING signaling may contribute to the activation of the NLRP3 inflammasome and pyroptosis-associated injury. In diabetic rat model, therapeutic intervention with siRNAs targeting cGAS, STING, or NLRP3 significantly attenuated lens opacity and effectively improved histopathological alterations in the lens epithelium and cortex. Collectively, these findings indicate that HG promotes cytosolic DNA accumulation, and the cGAS-STING and NLRP3 signaling may represent a potentially important inflammatory pathway involved in pyroptosis-associated injury in DC. Inhibition of the cGAS-STING signaling or NLRP3 inflammasome may represent a promising therapeutic strategy for DC.