Circ_0000756 Mediates Oxidative Stress and Metabolic Memory in Diabetic Neuropathy via miR-7b Suppression of NRF2/ARE Pathway.

Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes, in which oxidative stress and metabolic memory drive progressive nerve damage. Circular RNAs (circRNAs) have emerged as important regulators in diabetic complications, but their roles in DPN remain poorly understood. RNA sequencing (RNA-Seq) and Weighted Gene Co-Expression Network Analysis (WGCNA) were performed to identify DPN-associated circRNAs in rat sciatic nerves. Multi-omics approaches, including proteomics and metabolomics, were applied to characterize the downstream pathways of circ_0000756. Functional studies in Schwann cells assessed oxidative stress, apoptosis, and inflammatory responses, while a DPN rat model was used to validate in vivo effects. Circ_0000756 was significantly upregulated in DPN, acting as an miR-7b decoy to inhibit NRF2/ARE pathway activation. This led to enhanced oxidative stress, Schwann cell damage, and amplification of metabolic memory effects. Knockdown of circ_0000756 reduced oxidative stress and apoptosis in Schwann cells and mitigated nerve damage in DPN models. Circ_0000756 drives DPN progression by disrupting the miR-7b/NRF2/ARE axis, highlighting its potential as a therapeutic target for this challenging diabetic complication.