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

Article Article scientifique Article Hepatoprotective role for ERMP1 in MASLD-driven hepatocarcinogenesis and β-catenin-mutated tumors eng 2026-03-11 author Gjorgjieva Ducros Monika 0000-0001-8553-7525 Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Electronic address: monika.gjorgjieva@unige.ch. 891816 Département de physiologie cellulaire et métabolisme (PHYME) Monika Gjorgjieva author Correia De Sousa Marta Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Electronic address: marta.sousa@unige.ch. 910172 author Delangre Etienne Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 983567 Département de chirurgie (CHIRU) author Abegg Daniel Department of Chemistry, University of Illinois Chicago, Chicago, IL, USA. author Maeder Garavaglia Christine Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 22210 author Fournier Margot Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 134287 Département de chirurgie (CHIRU) author Morin Noëlie Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 977257 Département de physiologie cellulaire et métabolisme (PHYME) author Adibekian Alexander Department of Chemistry, University of Illinois Chicago, Chicago, IL, USA. author Serra Fulvia Institute of Pathology, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland. author Sempoux Christine Institute of Pathology, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland. author Maechler Pierre 0000-0002-2005-1433 Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 76515 Département de physiologie cellulaire et métabolisme (PHYME) author Foti Michelangelo Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 740312 218427 10.1016/j.canlet.2026.218427 41825847 0304-3835 https://www.sciencedirect.com/science/article/pii/S0304383526001904 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. ERMP1 HCC MASLD Lipid metabolism Β-catenin-mutated tumors Dewey 612 Swiss National Science Foundation Tumour bioenergetic: ERMP1 in MAFLD-driven liver cancer 215041 CH 134 Département de physiologie cellulaire et métabolisme 21C false 472 Obésité et syndrome métabolique 803 402 Mitochondries et métabolisme énergétique 671 https://doi.org/10.26037/yareta:yt64iklmdvenpl6ibzc73wh6ze Cancer letters 647 92033538-031d-487a-bcbe-a9818055a49e Article (Published version) Public 1-s2.0-S0304383526001904-main.pdf 18839909 application/pdf CC BY-4.0 0518f5de292d2c2922a7e5384671f908ce253b88c02aa5ccabb7504e7ef94cc0 cd85ebdb-8ad0-437b-b65a-6554c8dd4791 Supplemental data Public 1-s2.0-S0304383526001904-mmc1.xlsx 716431 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet a684b3dc432f2400162e265d2a710bc687c9c769a3094cc13a5defc32c40c533 f185584c-0138-44b2-8929-4de6ee664fd2 Supplemental data Public 1-s2.0-S0304383526001904-mmc2.xlsx 326716 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 74ab55f8dffdcf16a14a8cc89bbf4e46ea296fbded9df57416fd64c781a2a740 06e457a3-c00a-4476-bc82-7d34d3c5fe55 Supplemental data Public 1-s2.0-S0304383526001904-mmc3.docx 6954158 application/vnd.openxmlformats-officedocument.wordprocessingml.document d4add12a23740d4bff4f824c7c6fc68d521b069e5b46fc5dd092fd9a87ee3864 openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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Hepatoprotective role for ERMP1 in MASLD-driven hepatocarcinogenesis and β-catenin-mutated tumors	Cancer letters			2026	21	38

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Foti, Michelangelo