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. 2025 Sep;44(34):3096-3112.
doi: 10.1038/s41388-025-03474-1. Epub 2025 Jul 1.

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

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

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

Yongbo Luo et al. Oncogene. 2025 Sep.

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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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All patients who provided tissue samples before enrollment also provided written informed consent. Human studies and animal experiments were approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) and Welfare Ethics Committee of the Experimental Animal Platform of the Academy of Medical Sciences at Zhengzhou University (Zhengzhou, China).

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