Wang Mengyao, Wen Xiao, Feng Zian, Choubey Mayank, Chen Shasha, Pan Ruru, Gong Ke, Tirumalasetty Munichandra Babu, Gao Fei, Liao Chenzhong, Yin Zequn, Zhang Shuang, He Yong, Chen Houzao, Cao Yang, Miao Qing Robert, Hu Wenquan, Duan Yajun
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.
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.
Nat Commun. 2025 Jul 1;16(1):5491. doi: 10.1038/s41467-025-61067-8.
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.
乙酸盐是酒精代谢的终产物。酰基辅酶A合成酶短链家族成员2（ACSS2）将乙酸盐转化为乙酰辅酶A，涉及代谢途径和表观遗传调控。然而，ACSS2介导的表观遗传控制在酒精性肝病（ALD）中的作用仍未完全明确。我们证明酒精会下调肝脏中的ACSS2，导致肝脏和血清中乙酸盐积累。这会扰乱铁代谢和肝脏铁死亡，引发肝损伤和炎症。从机制上讲，ACSS2与CREB结合蛋白（CBP）结合，介导组蛋白乙酰化并调节铁调素抗菌肽1/2（HAMP1/2）的转录。ACSS2缺乏会下调HAMP1/2，导致全身铁稳态失衡和铁死亡，而HAMP1/2的过表达可恢复这种状态。铁螯合剂或铁死亡抑制剂可减轻ACSS2缺陷小鼠的酒精性肝损伤。我们的研究揭示了ACSS2介导铁死亡的表观遗传机制及其在ALD进展中的作用。
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