SIRT5-mediated FDX1 desuccinylation confers cuproptosis resistance in lung adenocarcinoma

  • Cell Rep. 2026 Jun 23;45(6):117481. doi: 10.1016/j.celrep.2026.117481.
Qifan Hu  1 ,  Zuorui Wang  2 ,  Wenxin Deng  3 ,  Lei Wang  2 ,  Jiayuan Chen  3 ,  Hui Wang  4 ,  Lei Jiang  5 ,  Zhuo Lu  6 ,  Yikai Zhao  7 ,  Jia Hou  3 ,  Mingxi Gan  3 ,  Jing Xu  3 ,  Yaoguang Hua  3 ,  Yi Yuan  8 ,  Menglin Huang  3 ,  Lanxi Bai  3 ,  Jian-Bin Wang  9 ,  Bentong Yu  10
Affiliations
  • 1. Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China; China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang 330000, Jiangxi, China; Postdoctoral Research Station, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
  • 2. Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China; School of Basic Medical Sciences, Nanchang University, Nanchang 330031, Jiangxi, China.
  • 3. School of Basic Medical Sciences, Nanchang University, Nanchang 330031, Jiangxi, China.
  • 4. Department of Rehabilitation, The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang 330006, China.
  • 5. Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China; China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang 330000, Jiangxi, China.
  • 6. Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China.
  • 7. Westlake University, Hangzhou 310030, China.
  • 8. School of Huankui Academy, Nanchang University, Nanchang, Jiangxi 330031, China.
  • 9. Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China; School of Basic Medical Sciences, Nanchang University, Nanchang 330031, Jiangxi, China. Electronic address: [email protected].
  • 10. Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China; China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang 330000, Jiangxi, China. Electronic address: [email protected].
PMID: 42228571 DOI: 10.1016/j.celrep.2026.117481
Abstract

Cuproptosis, a copper-dependent cell death process induced by excessive copper, represents an emerging therapeutic strategy in oncology. However, tumor-specific molecular pathways regulating this process remain poorly defined. Here, we demonstrate that copper levels are elevated in lung adenocarcinoma (LUAD), and LUAD cell lines exhibit increased resistance to Cuproptosis. Mechanistically, elevated copper stress promotes the expression of the desuccinylase SIRT5 while reducing global succinylation in LUAD cells. Furthermore, we found that SIRT5 is a critical mediator of Cuproptosis through the desuccinylation modification on ferredoxin1 (FDX1) protein at Lys84. This modification triggers TRIM8-mediated ubiquitination, leading to FDX1 proteasomal degradation and enhanced Cuproptosis resistance. These results reveal the important role of SIRT5 in LUAD Cuproptosis resistance. Notably, combining the SIRT5 Inhibitor MC3482 with the Cuproptosis Inducer Elesclomol-Cu synergistically suppresses tumor growth in vivo, suggesting a promising therapeutic strategy. These findings elucidate mechanisms underlying Cuproptosis resistance and propose a novel treatment approach for LUAD.

Keywords
CP: cancer; CP: molecular biology; FDX1; SIRT5; cuproptosis; lung adenocarcinoma; succinylation.
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