Hepatoprotective role for ERMP1 in MASLD-driven hepatocarcinogenesis and β-catenin-mutated tumors

Metabolic dysfunction-associated steatotic liver disease (MASLD) ranges from simple steatosis to steatohepatitis and fibrosis, with cirrhosis and hepatocellular carcinoma (HCC) as end-stage complications. Beyond gene mutations, altered expression of metabolism-related genes contributes to MASLD progression toward HCC. We identified the poorly characterized endoplasmic reticulum metallopeptidase 1 (ERMP1) as upregulated in MASLD and HCC. This study aimed to define ERMP1's function in MASLD and HCC progression. ERMP1 expression was assessed in silico in human HCC cohorts and mouse models. ERMP1 was knocked out or silenced in complementary in vivo and in vitro systems to evaluate its metabolic and oncogenic roles. ERMP1 upregulation in human HCC correlated with advanced stage and poor survival. MASLD/HCC mouse models also showed increased hepatic/tumoral ERMP1 expression. Hepatic Ermp1 loss increased tumor burden in lipid-dependent (LPTENKO) and Myc/β-catenin-driven HCC, with higher incidence observed in the former, but reduced tumorigenesis in Myc/p53-driven and DEN-induced HCC. Ermp1 deficiency also worsened diet-induced steatosis and elevated HDL cholesterol. Liver proteomics of LPTENERMP1KO mice revealed depletion of DNA repair, structural, and cell differentiation proteins and enrichment of cholesterol transport and bile acid pathways. In vitro, ERMP1 silencing in human HCC cells impaired adhesion and migration, triggered apoptosis, enhanced chemotherapy sensitivity, and altered lipid secretion/trafficking. ERMP1 plays a protective role in MASLD and β-catenin-driven HCC by modulating lipid metabolism, but may support tumor progression after transformation. Its dual role highlights ERMP1 as a promising diagnostic and prognostic biomarker in MASLD-related HCC.