Wu Jiajun, Qin Tianyu, Han Weitao, Zhang Chao, Zhang Xiaohe, Huang Zhengqi, Wu Yuliang, Xu Yichun, Xu Kang, Ye Wei
Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510530, China; Department of Spine Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510289, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510289, China.
Department of Spine Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510289, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510289, China; Department of Spine Surgery, Orthopaedic, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University. the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
Free Radic Biol Med. 2025 Feb 16;228:93-107. doi: 10.1016/j.freeradbiomed.2024.12.043. Epub 2024 Dec 20.
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 (Fe) 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 Fe 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 Fe homeostasis and ultimately revitalize intervertebral discs.
椎间盘退变（IDD）与腰痛（LBP）的发病机制密切相关。在无血管环境中，氨基酸代谢对髓核（NP）细胞平衡和椎间盘（IVD）完整性起到了显著的支持作用。然而，IDD进展过程中的具体代谢需求尚未完全明确。我们的研究表明，谷氨酰胺酶1（GLS1）作为调节谷氨酰胺代谢的关键酶，对于减轻NP细胞铁死亡、衰老以及IDD进展至关重要。我们的研究结果显示，GLS1过表达可调节谷氨酰胺代谢，减少NP细胞基质降解、铁死亡和衰老。从机制上讲，GLS1与NFS1相互作用并调节亚铁离子（Fe）稳态。GLS1驱动的谷氨酰胺代谢促进乙酰辅酶A的产生，这对于NFS1的组蛋白乙酰化很重要。因此，通过基因过表达恢复GLS1活性以维持铁稳态是减轻基质降解、铁死亡和衰老以及使椎间盘恢复活力的一种有前景的方法。总体而言，我们的数据提出了一个模型，其中GLS1介导的谷氨酰胺代谢与NP细胞基质降解、铁死亡和衰老相关，并且可以靶向NFS1以维持铁稳态并最终使椎间盘恢复活力。
