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ACSS2 protects against alcohol-induced hepatocyte ferroptosis through regulation of hepcidin expression

Author

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  • Mengyao Wang

    (University of Science and Technology of China
    Hefei University of Technology)

  • Xiao Wen

    (Chongqing Medical University)

  • Zian Feng

    (University of Science and Technology of China)

  • Mayank Choubey

    (New York University Grossman Long Island School of Medicine)

  • Shasha Chen

    (Hefei University of Technology)

  • Ruru Pan

    (Hefei University of Technology)

  • Ke Gong

    (Hubei University of Medicine)

  • Munichandra Babu Tirumalasetty

    (New York University Grossman Long Island School of Medicine)

  • Fei Gao

    (Capital Medical University)

  • Chenzhong Liao

    (Hefei University of Technology)

  • Zequn Yin

    (University of Science and Technology of China)

  • Shuang Zhang

    (Hefei University of Technology)

  • Yong He

    (Shanghai Institute of Medicine of Chinese Academy of Medical Sciences)

  • Houzao Chen

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yang Cao

    (University of Science and Technology of China)

  • Qing Robert Miao

    (New York University Grossman Long Island School of Medicine)

  • Wenquan Hu

    (Chongqing Medical University)

  • Yajun Duan

    (University of Science and Technology of China)

Abstract

Acetate is the end product of alcohol metabolism. Acyl-CoA synthetase short-chain family member 2 (ACSS2) converts acetate to acetyl-CoA, involving metabolic pathways and epigenetic regulation. However, the function of ACSS2-mediated epigenetic control in alcoholic liver disease (ALD) remains incompletely understood. We demonstrate that alcohol downregulates hepatic ACSS2, causing acetate accumulation in the liver and serum. This disrupts iron metabolism and hepatic ferroptosis, triggering liver injury and inflammation. Mechanistically, ACSS2 binds CREB binding protein (CBP) to mediate histone acetylation and regulate hepcidin antimicrobial peptide 1/2 (HAMP1/2) transcription. ACSS2 deficiency downregulates HAMP1/2, causing systemic iron dyshomeostasis and ferroptosis, which is restored by overexpression of HAMP1/2. Iron chelators or ferroptosis inhibitors attenuates alcohol-induced liver injury in ACSS2-deficient mice. Our study uncovers the epigenetic mechanisms of ACSS2-mediated ferroptosis and its role in ALD progression.

Suggested Citation

  • Mengyao Wang & Xiao Wen & Zian Feng & Mayank Choubey & Shasha Chen & Ruru Pan & Ke Gong & Munichandra Babu Tirumalasetty & Fei Gao & Chenzhong Liao & Zequn Yin & Shuang Zhang & Yong He & Houzao Chen &, 2025. "ACSS2 protects against alcohol-induced hepatocyte ferroptosis through regulation of hepcidin expression," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61067-8
    DOI: 10.1038/s41467-025-61067-8
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