2. Academic Validation
  3. ACSL5 regulated acetyl-CoA to promote bladder cancer cellular senescence via 53BP1 acetylation

ACSL5 regulated acetyl-CoA to promote bladder cancer cellular senescence via 53BP1 acetylation

  • Oncogene. 2025 Sep;44(34):3096-3112. doi: 10.1038/s41388-025-03474-1.
Yongbo Luo # 1 2 3,  Youmiao Zeng # 1 2 3 4,  Yuanhao Liu # 1 2 3,  Sheng Liu 5,  Yiheng Dai 1 2 3,  Wenbang Pan 1 2 3,  Lailai Zhang 1 2 3,  Ronghui Zhu 1 2 3,  Dapeng Feng 1 2 3,  Kaixuan Du 1 2 3,  Xuepei Zhang 1,  Bin Jia 6,  Fengyan Tian 7,  Lijie Zhou 8 9 10,  Chaohui Gu 11 12 13
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 2 Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 3 Unit of Day Surgery Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 4 Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 5 Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China.
  • 6 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. fccjiab@zzu.edu.cn.
  • 7 Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. fccguzh@zzu.edu.cn.
  • 8 Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. zhouxiaozhou29@126.com.
  • 9 Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. zhouxiaozhou29@126.com.
  • 10 Unit of Day Surgery Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. zhouxiaozhou29@126.com.
  • 11 Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. fcctianfy@zzu.edu.cn.
  • 12 Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. fcctianfy@zzu.edu.cn.
  • 13 Unit of Day Surgery Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. fcctianfy@zzu.edu.cn.
  • # Contributed equally.
PMID: 40595416 DOI: 10.1038/s41388-025-03474-1
Abstract

Disruption of the fatty acid oxidation process (FAO) significantly affects the tumorigenesis of bladder Cancer (BC). We found that long-chain fatty acid synthase 5 (ACSL5) acting as a key enzyme in the initial stage of FAO, was downregulated in BC, and the decreased level of ACSL5 was strongly associated with a poor prognosis for BC patients. Mechanistically, ACSL5 is highly methylated CpG islands in its DNA, which is regulated by DNA Methyltransferase 1 (DNMT1). ACSL5 promotes FAO, and reduces the intracellular lipid content while increasing the level of acetyl-CoA. Acetyl-CoA improves K1360 acetylation of TP53-binding protein 1 (53BP1), subsequently enhancing the recruitment of the P53-P21 senescent signaling axis in the nucleus and promoting cellular senescence. ACSL5 overexpression promoted BC senescence and inhibited BC cell proliferation, and elaidic acid (EA) feeding further enhanced these effects in vitro and in vivo. In summary, our study revealed that ACSL5-mediated lipid oxidation increases the acetyl-CoA content, promotes cellular senescence, and inhibits the proliferation of BC. The activation of ACSL5-mediated lipid oxidation to regulate cellular senescence may provide an innovative direction for BC therapy.

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