Glutarate ameliorates intervertebral disc degeneration by regulating ferroptosis through Nrf2 glutarylation

Metabolic disorders are major pathogenic factors contributing to IVDD, which is often associated with the accumulation of metabolic by-products. Elevated levels of glutarate have been observed in degenerated discs; however, its functional role and the underlying mechanisms remain unclear. This study aimed to elucidate the biological role of glutarate in IVDD and to uncover the underlying molecular mechanisms involved. We first investigated the effects of glutarate under both physiological and pathological conditions in NP cells. Our results showed that glutarate exhibited no significant cytotoxicity at concentrations below 2.0 mM and effectively attenuated TNF-α-induced death of NP cells. Transcriptomic analysis further suggested that glutarate exerts its protective effects primarily by inhibiting ferroptosis. Mechanistic studies revealed that knockdown of SUGCT significantly attenuated the anti-ferroptotic effects of glutarate, while reduction of protein glutarylation similarly diminished its protective activity. These findings indicate that glutarylation is critical in glutarate-mediated ferroptosis resistance. Enrichment analysis of transcription factors shared among differentially expressed genes (DEGs) identified Nrf2 as a key regulator. We further demonstrated that Nrf2 is a target of glutarylation, and that its glutarylation promotes dissociation from Keap1, followed by nuclear translocation. This process suppresses iron overload and lipid peroxidation, ultimately protecting cells against ferroptosis-induced injury. This study reveals that glutarate exerts a protective effect against IVDD, mediated by the SUGCT-Nrf2 glutarylation axis. Our findings highlight the importance of metabolic signaling in maintaining intervertebral disc homeostasis and provide new insights into potential metabolic targets for the treatment of degenerative disc disease.