DLL1 promotes diabetic cataract progression by driving epithelial-mesenchymal transition (EMT) via activation of the Notch signaling pathway.

Diabetic cataracts (DCs) are a major vision-threatening complication of diabetes mellitus; however, their molecular mechanisms remain incompletely understood. The present study aimed to investigate the role of the Notch ligand δ-like ligand 1 (DLL1) in the pathogenesis of DCs. Immunohistochemical analysis revealed elevated DLL1 expression in anterior lens capsule tissues from patients with DCs compared with patients with age-related cataracts. In vitro, high-glucose treatment combined with TGF-β2 treatment induced epithelial-mesenchymal transition (EMT) in human lens epithelial cells (HLEB3), and this was accompanied by increased DLL1 expression. Knockdown of DLL1 significantly suppressed TGF-β2-induced cell proliferation, migration and EMT, as evidenced by restored E-cadherin levels and reduced fibronectin and vimentin levels. Furthermore, the effects of DLL1 knockdown were enhanced by pharmacological inhibition of Notch signaling using N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), confirming that DLL1 exerted its effects via the Notch pathway. In a streptozotocin-induced diabetic rat model, intravitreal administration of DLL1 small interfering RNA markedly attenuated lens opacity progression, improved lens histo-architecture, and downregulated the expression levels of EMT markers and Notch downstream targets (hes family bHLH transcription factor 1 and hes related family bHLH transcription factor with YRPW motif 1). Collectively, these findings demonstrated that DLL1 promoted DC progression by driving EMT via activation of the Notch signaling pathway. Therefore, targeting DLL1-mediated Notch signaling may potentially play a role in delaying or preventing DCs, although further studies are needed.