2. Academic Validation
  3. SIRT5-mediated BCAT1 desuccinylation and stabilization leads to ferroptosis insensitivity and promotes cell proliferation in glioma

SIRT5-mediated BCAT1 desuccinylation and stabilization leads to ferroptosis insensitivity and promotes cell proliferation in glioma

  • Cell Death Dis. 2025 Apr 7;16(1):261. doi: 10.1038/s41419-025-07626-9.
Tao Wang 1,  Xin-Hao Han 2,  Jun-Jun Chen 2,  Xing Wang 3,  Zhen Zhang 4,  Xiao-Jian Han 2,  Zhuo Lu 5 6
Affiliations

Affiliations

  • 1 Institute of Geriatrics, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China. wangtaoalepellis@gmail.com.
  • 2 Institute of Geriatrics, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China.
  • 3 Centre for Medical Research and Translation, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China.
  • 4 Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China.
  • 5 Department of Thoracic Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China. ndyfy10004@ncu.edu.cn.
  • 6 Jiangxi Hospital of China-Japan Friendship Hospital, National Regional Center for Respiratory Medicine Nanchang, Nanchang, Jiangxi, China. ndyfy10004@ncu.edu.cn.
PMID: 40195331 DOI: 10.1038/s41419-025-07626-9
Abstract

Glioma is a highly aggressive brain tumor with limited treatment success due to its resistance to conventional therapies. Sirtuin 5 (SIRT5) has emerged as a promising target for Cancer therapy, though it exhibits dual roles in different Cancer types. In this study, we investigate the role of SIRT5 in glioma and its corresponding mechanisms. Our findings demonstrate that SIRT5 expression is elevated in glioma cells both in vitro and in vivo. SIRT5 knockdown significantly reduced glioma cell proliferation and enhanced sensitivity to Ferroptosis. Proteomic and metabolomic analyses identifies branched-chain amino acid (BCAA) metabolism as a key downstream pathway regulated by SIRT5 through branched-chain aminotransferase 1 (BCAT1). Specifically, SIRT5-mediated desuccinylation of BCAT1 at K39 inhibits its interaction with the E3 Ligase CHIP, thereby preventing BCAT1 degradation via the ubiquitin-proteasome system. Moreover, BCAT1 overexpression reverses the proliferation inhibition and Ferroptosis sensitivity observed in SIRT5-knockdown cells. Clinically, we reveal a positive correlation between SIRT5 and BCAT1 levels in glioma samples, with higher expression levels predicting more advanced glioma grades and poorer clinical outcomes. Collectively, this study highlights the critical role of SIRT5 in promoting glioma progression via metabolic regulation and Ferroptosis insensitivity, offering a potential therapeutic target for glioma treatment.

Figures
Products
Inhibitors & Agonists
Other Products