SCF-cyclin F ubiquitin ligase attenuates diabetic kidney disease podocyte injury by targeting EIF4A3 for ubiquitination and degradation to suppress circ_0000285 expression

Diabetic kidney disease (DKD), a leading cause of end-stage renal disease, is characterized by podocyte injury. Although circular RNAs are emerging as important disease regulators, the role of circ_0000285 in DKD-associated podocyte injury remains unclear. Our study was designed to explore the role of circ_0000285 in DKD-associated podocyte injury. RNA pull-down confirmed the EIF4A3-circ_0000285 binding. qRT-PCR analysis assessed expression levels of circ_0000285, EIF4A3, and cyclin F. Western blot assay was employed to determine protein expression of Bcl-2, Bax, EIF4A3, and cyclin F. Cell proliferation and apoptosis were assessed via EdU assay and flow cytometry, respectively. Inflammation and oxidative stress were assessed with commercial kits. Intracellular ROS were measured using DCFH-DA probes. Co-IP examined the EIF4A3-cyclin F interaction and EIF4A3 ubiquitination. Renal function and podocyte damage were analyzed via H&E staining and PAS staining. Immunohistochemistry was employed to detect expression of desmin, synaptopodin and EIF4A3. EIF4A3 binds to Circ_0000285 and promotes its expression. EIF4A3 and Circ_0000285 were significantly upregulated in HG-stimulated MPC-5 cells. Under HG conditions, cell proliferation was markedly inhibited, while apoptosis, inflammatory response, and oxidative stress were enhanced. However, these phenotypes were partially reversed by EIF4A3 knockdown. Mechanistically, Cyclin F interacts with EIF4A3 and facilitates its ubiquitination and degradation. Cyclin F was downregulated in HG-induced MPC-5 cells, whereas Cyclin F overexpression ameliorated renal injury, suppressed inflammation and oxidative stress, and improved renal function in vivo and in vitro, accompanied by reduced levels of EIF4A3 and circ_0000285. Cyclin F attenuates podocyte injury by promoting EIF4A3 ubiquitination and degradation, thereby downregulating circ_0000285, which supports the Cyclin F/EIF4A3/circ_0000285 regulatory axis and provides a potential therapeutic target for DKD.