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

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

  • Free Radic Biol Med. 2025 Feb 16:228:93-107. doi: 10.1016/j.freeradbiomed.2024.12.043.
Jiajun Wu 1,  Tianyu Qin 2,  Weitao Han 3,  Chao Zhang 3,  Xiaohe Zhang 3,  Zhengqi Huang 3,  Yuliang Wu 3,  Yichun Xu 4,  Kang Xu 5,  Wei Ye 6
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510530, China. Electronic address: xuyichun18@163.com.
  • 5 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. Electronic address: xukang@mail.sysu.edu.cn.
  • 6 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. Electronic address: yewei3@mail.sysu.edu.cn.
PMID: 39710108 DOI: 10.1016/j.freeradbiomed.2024.12.043
Abstract

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.

Keywords

Ferroptosis; GLS1; Glutamine metabolism; Intervertebral disc degeneration; Oxidative stress; Senescence.

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