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

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, Yang Cao, Qing Robert Miao, Wenquan Hu () and Yajun Duan ()
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Mengyao Wang: University of Science and Technology of China
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

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61067-8

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