NAT10 promotes gallbladder cancer progression by remodeling cholesterol metabolism via PCSK9 mRNA acetylation

  • Cell Death Discov. 2026 Apr 16;12(1):251. doi: 10.1038/s41420-026-03104-z.
Zheng-Yu Chen  #  1  2 ,  Ming-Yang Wang  #  1  2 ,  Ben Ma  #  3 ,  Cheng Zhao  1  2 ,  Li-Jia Pan  1  2 ,  Zi-Ying Wang  1  2 ,  Yu-Ting Wang  1  2 ,  Pan-Yi Mao  1  2 ,  Xiang Zhao  1  2 ,  De-Long Qin  1  2 ,  Yi-Jun Shu  4  5 ,  Yun-Jiao Zhang  6 ,  Shan-Shan Xiang  7  8 ,  Ping Dong  9  10
Affiliations
  • 1. Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. Shanghai Key Laboratory of Biliary Tract Disease Research, China, Shanghai, China.
  • 3. Department of Gastrointestinal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 4. Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 5. Shanghai Key Laboratory of Biliary Tract Disease Research, China, Shanghai, China. [email protected].
  • 6. Department of Cardio-Thoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China. [email protected].
  • 7. Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 8. Shanghai Key Laboratory of Biliary Tract Disease Research, China, Shanghai, China. [email protected].
  • 9. Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 10. Shanghai Key Laboratory of Biliary Tract Disease Research, China, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41991932 DOI: 10.1038/s41420-026-03104-z
Abstract

Gallbladder Cancer (GBC) is a highly aggressive biliary tract tumor with a poor prognosis, underscoring the critical need for new therapeutic strategies. N-acetyltransferase 10 (NAT10), the sole writer of N4-acetylcytidine (ac4C), is upregulated in multiple cancers and is implicated in tumor pathogenesis. We observed significant NAT10 overexpression in GBC. Functional studies confirmed that NAT10 drives growth, migration, and malignant progression of GBC cells. We mechanistically linked this to NAT10-mediated ac4C modification, which stabilizes proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA, thereby reprogramming Cholesterol metabolism and triggering intracellular Cholesterol accumulation. This Cholesterol buildup subsequently activates the PI3K/Akt pathway, stimulating Cancer cell proliferation, migration, and invasion. Therapeutically, targeting NAT10 with Remodelin potently suppressed GBC proliferation. Importantly, Remodelin synergized with the standard chemotherapeutic agent gemcitabine to markedly enhance its therapeutic effect. Thus, our study defines a novel mechanism in which NAT10-dependent ac4C modification stabilizes PCSK9 mRNA to promote cholesterol-driven malignancy, nominating NAT10 as a compelling therapeutic target in GBC.

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