Related Experiment Video
Updated: Apr 10, 2026
Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
LPCAT3 deficiency Drives phospholipid remodeling and mitochondrial oxidative dysfunction to accelerate MASH-HCC
Gaoxuan Shao1, Chenhao Ye2, Chenceng Sun2
1Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine), Shanghai 200032, China; Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai 200032, China.
Introduction:
Metabolic dysfunction-associated steatohepatitis (MASH) represents a severe subtype of metabolic dysfunction-associated fatty liver disease (MAFLD), characterized by hepatic steatosis, chronic inflammation, with or without fibrosis. Without appropriate intervention, MASH can progress to hepatocellular carcinoma (HCC). Lysophosphatidylcholine acyltransferase 3 (LPCAT3), an endoplasmic reticulum membrane protein regulating phospholipid composition, is critical for maintaining endoplasmic reticulum and mitochondrial homeostasis. However, its role in MASH-to-HCC progression remains unclear.
Objectives:
To investigate the mechanism by which LPCAT3 influences the progression from MASH to HCC.
Methods:
LPCAT3 expression levels were examined in tumor and adjacent non-tumor tissues from patients with MASH-associated HCC. A MASH-HCC mouse model was established using a high-fat, high-cholesterol diet, and lipidomics and proteomics analyses were performed to elucidate the role of LPCAT3 in MASH-HCC progression. In addition, a liver-specific LPCAT3 knockout mouse model was generated, and LPCAT3 was overexpressed in mouse livers using an adeno-associated virus (AAV) system to evaluate its role in the development of MASH-HCC.
Results:
Our study revealed that hepatic LPCAT3 expression was markedly reduced in mice fed a high-fat, high-cholesterol diet. Liver-specific LPCAT3 deficiency accelerates MASH progression, as evidenced by increased hepatic inflammation and fibrosis, and further promoted the transition from MASH to HCC over time. Mechanistically, LPCAT3 deficiency upregulated protein disulfide isomerase (Pdi)-endoplasmic reticulum oxidoreductase 1 alpha (Ero1α) expression, leading to mitochondrial accumulation of H2O2 and Ca2+ and impairing mitochondrial oxidative phosphorylation function. LPCAT3 deficiency also reduced PC (18:2/18:2) levels, whereas supplementing PC (18:2/18:2) in LPCAT3-knockdown cells reversed the upregulation of Pdi-Ero1α and alleviated mitochondrial H2O2 and Ca2+ accumulation. Furthermore, LPCAT3 overexpression ameliorated mitochondrial dysfunction and inhibited the progression from MASH to HCC in mice.
Conclusion:
LPCAT3 deficiency triggers Pdi-Ero1α-mediated mitochondrial dysfunction, identifying LPCAT3 as a promising therapeutic target for MASH-associated HCC.
