Beyond fibrosis: the molecular roadmap from MASLD to hepatocellular carcinoma.
8 affiliations
- 1Microscopic and Ultrastructural Anatomy Research Unit, Departmental Faculty of Medicine, Surgery and Dentistry, Università Campus Bio-Medico di Roma, Rome, Italy.
- 2Gastroenterology and Endoscopy Unit, Departmental Faculty of Medicine, Surgery and Dentistry, Università Campus Bio-Medico di Roma, Rome, Italy.
- 3Departmental Faculty of Science and Bio-Technology, Università Campus Bio-Medico di Roma, Rome, Italy.
- 4Operative Research Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
- 5Research Unit of Anatomical Pathology, Departmental Faculty of Medicine, Surgery and Dentistry, Università Campus Bio-Medico di Roma, Rome, Italy.
- 6Anatomical Pathology Operative Research Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
- 7Department of Pathology, Ospedale San Camillo Forlanini, Rome, Italy.
- 8Predictive Molecular Diagnostics, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has overtaken viral hepatitis as the fastest-growing cause of hepatocellular carcinoma (HCC) in most high-income countries. What makes this epidemic clinically treacherous is a feature that distinguishes MASLD-related HCC from other aetiologies: roughly half of all cases arise in livers that have never progressed to cirrhosis, slipping through the net of conventional surveillance strategies. The molecular journey from fatty liver to malignancy unfolds through at least six interlocking programmes: lipotoxic rewiring of hepatocyte metabolism, including acquired lysosomal acid lipase (LAL) dysfunction, oncogenic glucose reprogramming through the p53-PUMA-mitochondrial pyruvate carrier (MPC) axis, and a preliminary MLKL-Mfn2 axis linking metabolic stress to mitochondrial dysfunction; a chronic shift in the hepatic immune milieu toward tumour-permissive tolerance; gut microbiota dysbiosis flooding portal circulation with pro-inflammatory metabolites; progressive collapse of autophagic flux with p62/SQSTM1 accumulation and lipolysosome formation; and pervasive epigenetic rewriting spanning DNA methylation, novel histone marks, and non-coding RNA networks. We also discuss emerging biomarkers and therapeutic strategies, closing with a brief note on Doublecortin-like kinase 1 (DCLK1) as a candidate marker at the intersection of cancer stem cell identity and immune microenvironment subversion.
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BibTeX
@article{nevi2026beyond,
title = {{Beyond fibrosis: the molecular roadmap from MASLD to hepatocellular carcinoma.}},
author = {Lorenzo Nevi and Annamaria Altomare and Paolo Gallo and Chiara Taffon and Teresa Musarra and Andrea Baiocchini and Simone Carotti},
journal = {Frontiers in oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1933386},
url = {https://europepmc.org/article/MED/42899080},
note = {CC BY},
}
RIS
TY - JOUR
TI - Beyond fibrosis: the molecular roadmap from MASLD to hepatocellular carcinoma.
AU - Lorenzo Nevi
AU - Annamaria Altomare
AU - Paolo Gallo
AU - Chiara Taffon
AU - Teresa Musarra
AU - Andrea Baiocchini
AU - Simone Carotti
PY - 2026
DA - 2026/10/05
JO - Frontiers in oncology
DO - 10.3389/fonc.2026.1933386
UR - https://europepmc.org/article/MED/42899080
AB - Metabolic dysfunction-associated steatotic liver disease (MASLD) has overtaken viral hepatitis as the fastest-growing cause of hepatocellular carcinoma (HCC) in most high-income countries. What makes this epidemic clinically treacherous is a feature that distinguishes MASLD-related HCC from other aetiologies: roughly half of all cases arise in livers that have never progressed to cirrhosis, slipping through the net of conventional surveillance strategies. The molecular journey from fatty liver to malignancy unfolds through at least six interlocking programmes: lipotoxic rewiring of hepatocyte metabolism, including acquired lysosomal acid lipase (LAL) dysfunction, oncogenic glucose reprogramming through the p53-PUMA-mitochondrial pyruvate carrier (MPC) axis, and a preliminary MLKL-Mfn2 axis linking metabolic stress to mitochondrial dysfunction; a chronic shift in the hepatic immune milieu toward tumour-permissive tolerance; gut microbiota dysbiosis flooding portal circulation with pro-inflammatory metabolites; progressive collapse of autophagic flux with p62/SQSTM1 accumulation and lipolysosome formation; and pervasive epigenetic rewriting spanning DNA methylation, novel histone marks, and non-coding RNA networks. We also discuss emerging biomarkers and therapeutic strategies, closing with a brief note on Doublecortin-like kinase 1 (DCLK1) as a candidate marker at the intersection of cancer stem cell identity and immune microenvironment subversion.
SN - 2234-943X
ER -