SGLT2 inhibition attenuates cytoskeletal and proteostatic dysfunction through the AGE–RAGE–IGFBP2–FBN1 signaling axis in diabetic lenses

BACKGROUND AND PURPOSE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated pleiotropic protective effects beyond glycemic control; however, their pharmacological impact on cytoskeletal remodeling and proteostatic regulation remains poorly defined. This study investigated whether SGLT2 inhibition modulates cytoskeletal-proteostatic signaling through the AGE-RAGE axis in diabetic conditions. EXPERIMENTAL APPROACH: Transcriptomic profiling of human lens epithelial samples identified dysregulated signaling pathways associated with cytoskeletal organization and extracellular matrix remodeling. Streptozotocin-induced diabetic rats were treated with dapagliflozin for 12 weeks. Pharmacological effects were evaluated using slit-lamp examination, immunofluorescence, and western blot analysis targeting IGFBP2, FBN1, Rac1-GTP, Myosin IIB, cytoskeletal scaffolding proteins, and crystallin aggregation. KEY RESULTS: Diabetic conditions induced activation of the AGE-RAGE-IGFBP2-FBN1 signaling cascade, accompanied by Rac1-Myosin IIB-mediated cytoskeletal remodeling and proteostatic disruption. Pharmacological inhibition of SGLT2 significantly suppressed this signaling axis, restored cytoskeletal integrity, and reduced crystallin aggregation. These molecular changes were associated with delayed progression of lens opacity in vivo. CONCLUSIONS AND IMPLICATIONS: This study identifies a previously unrecognized pharmacological mechanism whereby SGLT2 inhibition modulates cytoskeletal and proteostatic homeostasis via the AGE-RAGE-IGFBP2-FBN1 pathway. These findings provide mechanistic support for drug repurposing of SGLT2 inhibitors as systemic modulators of diabetes-associated tissue dysfunction.