Ubiquitination-mediated PRDX2 alleviates intervertebral disc degeneration via restraining TBHP-induced nucleus pulposus cell apoptosis, ferroptosis and ECM degradation

Abstract Background Peroxiredogenase 2 (PRDX2) has been confirmed to be downregulated in patients with intervertebral disc degeneration (IDD). However, the role and mechanism of PRDX2 in the progression of IDD are still unclear. Methods Tert-butyl hydroperoxide (TBHP)-induced nucleus pulposus (NP) cells were used to construct IDD conditions. qRT-PCR or western blot was used to detect the expression levels of PRDX2, ubiquitin-specific protease 11 (USP11), ferroptosis-related markers and extracellular matrix (ECM)-related proteins. CCK8 assay, TUNEL assay and detection of ferroptosis-related markers were performed to examine cell viability, apoptosis and ferroptosis. Co-IP assay and ubiquitination assay were used to explore the regulation of USP11 on PRDX2. Results The expression levels of PRDX2 and USP11 were reduced in IDD patients and TBHP-induced NP cells. PRDX2 overexpression repressed TBHP-induced NP cell apoptosis, ferroptosis and ECM degradation. Moreover, our study found that USP11 stabilized the protein expression of PRDX2 by decreasing its ubiquitination. In addition, USP11 overexpression inhibited TBHP-induced NP cell apoptosis, ferroptosis and ECM degradation, while these effects were reversed by PRDX2 knockdown. Conclusion USP11-mediated deubiquitination of PRDX2 might alleviate IDD progression by inhibiting TBHP-induced NP cell apoptosis, ferroptosis and ECM degradation, providing a potential intervention target worthy of further research for IDD.