miR-188-5p delays intervertebral disc degeneration by mediating P4HB to regulate ferroptosis in nucleus pulposus cells

BackgroundIntervertebral disc degeneration (IDD) has the characteristics of global, high incidence and high disability rate, which brings heavy economic and psychological burden to patients. Current clinical treatments are not effective in slowing the progression of IDD. Ferroptosis is an important cause of IDD development.The mechanism by which miR-188-5p regulates ferroptosis in nucleus pulposus cells (NPCs) has not been reported.MethodsFirstly, bioinformatics was used to screen the miRNA and mRNA of differentially expressed genes in IDD. Then, clinical nucleus pulposus (NP) tissues were obtained for expression identification. TBHP induced ferroptosis in NPCs and detected the expression differences of miR-188-5p, P4HB and oxidative stress indicators, and verified the ability of transfection with miR-188-5p inhibitor to inhibit TBHP. Subsequently, the function of the miR-188-5p/P4HB axis was verified through experiments such as luciferase assay, cell transfection, and functional rescue. Finally, in vivo experiments were conducted to evaluate the ability of miR-188-5p to regulate IDD.ResultsBioinformatics combined with a series of histological, cytological and animal experiments revealed that miR-188-5p is important ferroptosis driver in nucleus pulposus cells(NPCs). Compared with normal nucleus pulposus (NP) tissues, miR-188-5p expression was up-regulated and P4HB was down-regulated in degraded NP tissues, and P4HB was the target gene of miR-188-5p. Transfection with miR-188-5p inhibitor significantly facilitated P4HB, SLC7A11 and GPX4 expression, which inhibited cell ferroptosis, apoptosis and promoted proliferation. Finally, the rat IDD model confirmed that miR-188-5p inhibitor significantly increased the height and signal intensity of the intervertebral space and inhibited the intervertebral disc degeneration in rats.ConclusionsCollectively, our findings establish miR-188-5p as a ferroptosis activator in IDD. Knockdown of miR-188-5p significantly upregulated P4HB expression, suppressed ferroptosis, and attenuated IDD progression. This study identifies miR-188-5p as a potential therapeutic target, providing a novel mechanistic framework for IDD treatment strategies.