2. Academic Validation
  3. ACSS2 protects against alcohol-induced hepatocyte ferroptosis through regulation of hepcidin expression

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

  • Nat Commun. 2025 Jul 1;16(1):5491. doi: 10.1038/s41467-025-61067-8.
Mengyao Wang # 1 2,  Xiao Wen # 3,  Zian Feng 1,  Mayank Choubey 4,  Shasha Chen 2,  Ruru Pan 2,  Ke Gong 5,  Munichandra Babu Tirumalasetty 4,  Fei Gao 6,  Chenzhong Liao 2,  Zequn Yin 1,  Shuang Zhang 2,  Yong He 7,  Houzao Chen 8,  Yang Cao 1,  Qing Robert Miao 4,  Wenquan Hu 9,  Yajun Duan 10
Affiliations

Affiliations

  • 1 Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 2 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.
  • 3 Center for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 4 Department of Foundations of Medicine, New York University Grossman Long Island School of Medicine, Mineola, NY, USA.
  • 5 Department of Physiology, Faculty of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, Hubei, China.
  • 6 Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
  • 7 Shanghai Institute of Medicine of Chinese Academy of Medical Sciences, Shanghai, China.
  • 8 Department of Biochemistry and Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 9 Center for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. huwenquan2002@163.com.
  • 10 Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. yajunduan@ustc.edu.cn.
  • # Contributed equally.
PMID: 40593779 DOI: 10.1038/s41467-025-61067-8
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.

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