LPCAT3 deficiency Drives phospholipid remodeling and mitochondrial oxidative dysfunction to accelerate MASH-HCC development.
[INTRODUCTION] Metabolic dysfunction-associated steatohepatitis (MASH) represents a severe subtype of metabolic dysfunction-associated fatty liver disease (MAFLD), characterized by hepatic steatosis,
APA
Shao G, Ye C, et al. (2026). LPCAT3 deficiency Drives phospholipid remodeling and mitochondrial oxidative dysfunction to accelerate MASH-HCC development.. Journal of advanced research. https://doi.org/10.1016/j.jare.2026.04.018
MLA
Shao G, et al.. "LPCAT3 deficiency Drives phospholipid remodeling and mitochondrial oxidative dysfunction to accelerate MASH-HCC development.." Journal of advanced research, 2026.
PMID
41951050
Abstract
[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 HO and Ca 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 HO and Ca 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.
[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 HO and Ca 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 HO and Ca 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.