circKIAA1462 knockdown restores autophagy and suppresses pyroptosis in diabetic retinopathy via miR-183-5p/HMGB1 axis

Diabetic retinopathy (DR) is a leading cause of vision loss, stemming from diabetes complications. Early retinal pigment epithelium (RPE) dysfunction is a critical pathogenic event, but specific mechanisms driving its progression remain unclear. Circular RNAs (circRNAs) are emerging as important regulators in diabetic complications, often acting as microRNA sponges or influencing gene expression. Understanding the precise circRNA-mediated pathways in RPE injury could uncover novel therapeutic targets for DR, addressing the current limitations in preventing early disease progression.

Researchers identified differentially expressed circRNAs in ARPE-19 cells under normal and high glucose conditions using circular RNA microarray and RNA-seq. Expression levels of cKIAA1462, miR-183-5p, and HMGB1 were quantified via quantitative real-time polymerase chain reaction and Western blot. In vitro, flow cytometry, Western blot, and Electron microscope (TEM) assessed autophagy and pyroptosis. Binding interactions were confirmed using dual-luciferase reporter assays. In vivo, cKIAA1462 was knocked down via intravitreal lentiviral injection in diabetic mice, followed by expression analysis, functional assessments, and histological evaluations.

Under high glucose conditions, cKIAA1462 was significantly upregulated both in vitro (ARPE-19 cells) and in vivo (retinas of diabetic mice). This circRNA functioned as a molecular sponge for miR-183-5p, leading to increased expression of HMGB1. Elevated HMGB1 concurrently impaired autophagic flux, evidenced by increased p62 levels and decreased autophagosomes, while also activating the NLRP3 inflammasome. This activation was marked by upregulated NLRP3, ASC, and caspase-1, ultimately promoting pyroptosis in RPE cells. > Silencing cKIAA1462 in diabetic mice restored autophagy, suppressed pyroptosis, significantly improved retinal structure, and enhanced electroretinogram responses, indicating functional recovery.