Transcription factor EGR2 drives cataract formation through IGFBP3-mediated oxidative injury in lens epithelial cells.

Cataracts, a prevalent ocular disorder, represent the leading cause of global blindness. Evidence indicates that oxidative stress-induced lens epithelial cells (LECs) apoptosis constitutes a key pathogenic mechanism in age-related cataract (ARC). Although the transcription factor EGR2 has been recognized as both a novel senescence regulator and a critical mediator in ophthalmic diseases including uveitis and diabetic retinopathy, its precise role in cataract remains undefined. In this study, EGR2 was identified via transcriptome sequencing as a potential core regulator of cataract development. Subsequent investigations demonstrated elevated EGR2 expression in the anterior capsule from cataract patients, oxidatively damaged LECs, and a sodium selenite-induced rat cataract model. Functional studies revealed that EGR2 overexpression exacerbated oxidative stress and promoted apoptosis in LECs. Notably, intravitreal administration of AAV-shEGR2 significantly attenuated lens opacification. RNA-seq and CUT& Tag findings indicated that EGR2 directly bound to its downstream target insulin-like growth factor binding protein 3 (IGFBP3). Furthermore, IGFBP3 silencing effectively reversed EGR2-mediated oxidative injury and apoptosis in LECs, while administration of recombinant IGFBP3 protein accelerated cataract progression in vivo. This study delineates EGR2 as a pivotal regulator in cataract pathogenesis, proposing a novel therapeutic target while uncovering the molecular mechanism of oxidative stress-mediated lens pathology.