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, 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: 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.