GLS1-mediated glutamine metabolism mitigates oxidative stress-induced matrix degradation, ferroptosis, and senescence in nucleus pulposus cells by modulating Fe2+ homeostasis

• Published in: Free radical biology & medicine 2025-02, Vol.228, p.93-107
• Main Authors: Wu, Jiajun, Qin, Tianyu, Han, Weitao, Zhang, Chao, Zhang, Xiaohe, Huang, Zhengqi, Wu, Yuliang, Xu, Yichun, Xu, Kang, Ye, Wei
• Format: Article
• Language: English
• Subjects: Ferroptosis; GLS1; Glutamine metabolism; Intervertebral disc degeneration; Oxidative stress; Senescence
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2024.12.043

Intervertebral disc degeneration (IDD) is intricately linked to the pathogenesis of low back pain (LBP). The balance of nucleus pulposus (NP) cell and intervertebral disc (IVD) integrity is significantly supported by amino acid metabolism within an avascular milieu. However, the specific metabolic demands during the progression of IDD are not fully understood. Our study revealed that GLS1, a key enzyme that regulates glutamine metabolism, is key for mitigating NP cell ferroptosis, senescence, and IDD progression. Our findings show that GLS1 overexpression modulates glutamine metabolism, reducing NP cell matrix degradation, ferroptosis, and senescence. Mechanistically, GLS1 interacts with NFS1 and regulates ferrous ion (Fe2+) homeostasis. GLS1-driven glutamine metabolism facilitates acetyl-CoA production, which is important for the histone acetylation of NFS1. Thus, restoring GLS1 activity through gene overexpression to maintain Fe2+ homeostasis is a promising approach for mitigating matrix degradation, ferroptosis, and senescence and for rejuvenating intervertebral discs. Collectively, our data suggest a model in which GLS1-mediated glutamine metabolism is associated with NP cell matrix degradation, ferroptosis, and senescence and that NFS1 can be targeted to maintain Fe2+ homeostasis and ultimately revitalize intervertebral discs. •A reduction in GLS1 expression is observed in the progression of IDD.•Overexpression of GLS1 reduced ferroptosis and delayed senescence in nucleus pulposus cells.•The GLS1-NFS1 regulatory axis mitigates ferroptosis in nucleus pulposus cells by maintaining iron homeostasis.