Alleviative effect of microRNA-497 on diabetic neuropathic pain in rats in relation to decreased USP15

The current study tries to discuss the functional role of microRNA-497 (miR-497) in diabetic neuropathic pain (DNP) and the related downstream mechanism. Bioinformatics analysis was implemented for the identification of differentially expressed miRNAs and genes. DNP was simulated in rats through intraperitoneal injection of streptozotocin. The expression patterns of miR-497, USP15, NRF2, and G6PD were then determined. The binding of miR-497 and USP15 was confirmed. Using gain- and loss-of-function assays, we analyzed the critical role of miR-497-mediated USP15 in DNP through the NRF2/G6PD axis. Downregulated miR-497 and elevated USP15 were observed in the dorsal root ganglion neurons isolated from spinal cord tissues of STZ-induced DNP rats. miR-497 could alleviate DNP, which was associated with suppression of USP15, a confirmed target of miR-497. USP15 enhanced the degradation and ubiquitination of NRF2 and induced G6PD expression, leading to the progression of DNP. We highlighted the crucial role of miR-497-mediated USP15 in DNP through the NRF2/G6PD axis.Graphical abstract1. miR-497 is downregulated in DRG neurons from spinal cord tissues of STZ-induced DNP rats.2. miR-497 inhibits the expression of USP15, thereby alleviating STZ-induced DNP in rats.3. USP15 promotes ubiquitination and degradation of NRF2, reducing the expression of G6PD.4. miR-497 alleviates STZ-induced DNP in rats by regulating the USP15/NRF2/G6PD axis.