GPAM mediates mitochondrial dysfunction and the progression of alcoholic liver disease through lipid remodeling

  • Sci Adv. 2026 Jun 26;12(26):eaef1896. doi: 10.1126/sciadv.aef1896.
Zibin Zhan  1 ,  Xuewen Liu  2 ,  Zehua Li  1 ,  Xueyan Qiao  3 ,  Shuo Li  4 ,  Yu Gong  1 ,  Luping Yang  1 ,  Yi Gao  5 ,  Xianfeng Xia  6  7 ,  Kunhao Bai  1 ,  Fanhong Zeng  8 ,  Jun Weng  1  6
Affiliations
  • 1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
  • 2. Department of Thyroid Surgery, Huizhou Central People's Hospital, Huizhou, China.
  • 3. Department of Ultrasound, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 4. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 5. Guangdong Qianhui Biotechnology Co. Ltd., Guangzhou 510285, China.
  • 6. Department of Surgery and State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR 999077, People's Republic of China.
  • 7. Chow Yuk Ho Technology Center for Innovative Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, People's Republic of China.
  • 8. Department of Pathology and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.
PMID: 42341117 DOI: 10.1126/sciadv.aef1896
Abstract

Lipid metabolic disorders and mitochondrial dysfunction are key and core pathological processes that contribute to the progression of alcoholic Liver Disease (ALD). However, the effects of Lipid Metabolism disorders on mitochondrial dysfunction in patients with ALD remain unknown. Here, we demonstrated that glycerol-3-phosphateacyltransferase (GPAM) expression was down-regulated in patients with ALD and associated with ALD progression. Dysregulation of GPAM, a triglyceride synthetase, reshaped Lipid Metabolism by increasing the levels of toxic Lipids such as ceramide and lysophosphatidylcholine and reducing the levels of mitochondrial structural Lipids such as cardiolipin. These changes resulted in abnormal mitochondrial dynamics, impaired Mitophagy, and dysfunctional mitochondrial respiration, which induced activation of the cGAS-STING pathway. This activation resulted in the accumulation of inflammatory infiltrates, triggering the ALD process in mice. However, the reexpression of GPAM in vivo and in vitro and in hepatic organoids alleviated the development of ALD. This study aimed to determine whether GPAM is a potential therapeutic agent and assess the close relationship between Lipid Metabolism disorders and mitochondrial dysfunction in patients with ALD.

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