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Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment
Open accessAbstract
Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation, nonalcoholic steatohepatitis (NASH), has a global prevalence of 20-25% and is a major public health problem. Its incidence is increasing in parallel to the rise in obesity, diabetes and metabolic syndrome. Progression from NASH to NASH-related hepatocellular carcinoma (HCC) (~2% of cases per year) is influenced by many factors, including the tissue and immune microenvironment, germline mutations in PNPLA3, and the microbiome. NASH-HCC has unique molecular and immune traits compared with other aetiologies of HCC and is equally prevalent in men and women. Comorbidities associated with NASH, such as obesity and diabetes mellitus, can prevent the implementation of potentially curative therapies in certain patients; nonetheless, outcomes are similar in patients who receive treatment. NASH-HCC at the early to intermediate stages is managed with surgery and locoregional therapies, whereas advanced HCC is treated with systemic therapies, including anti-angiogenic therapies and immune-checkpoint inhibitors. In this Review, we present the latest knowledge of the pathogenic mechanisms and clinical management of NASH-HCC. We discuss data highlighting the controversy over varying responses to immune-checkpoint inhibitors according to underlying aetiology and suggest that the future of NASH-HCC management lies in improved surveillance, targeted combination therapies to overcome immune evasion, and identifying biomarkers to recognize treatment responders.
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“Reprogramming of liver microenvironment is a key feature of hepatocarcinogenesis, which encompasses but not limited to metabolic alterations of hepatocyte and immune cells, re-emergence of fetal-associated endothelial cells and altered inflammatory milieu [10, 46, 65, 66].”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [10]
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“Currently, there are no approved therapies for MASH [10]”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [10]
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“MASH promotes HCC through lipotoxicity, causing oxidative and endoplasmic reticulum stress, which induces inflammation and cell damage [14, 15] reactivation of molecular pathways such as Notch, Hedgehog, and YAP-TAZ in hepatocytes leads to inflammation, cell proliferation, and cancer [16].”
Metadata
- Authors
- Llovet, J. M., Willoughby, C. E., Singal, A. G., Greten, T. F., Heikenwälder, M., El-Serag, H. B., Finn, R. S., & Friedman, S. L.
- Affiliations
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Hospital Clínic de Barcelona (ES)
- The University of Texas Southwestern Medical Center (US)
- National Institutes of Health (US)
- German Cancer Research Center (DE)
- University of California, Los Angeles (US)
- Tisch Cancer Institute (US)
- Corresponding author
- Llovet, Josep M.
- ORCID
- Venue
- Nature Reviews Gastroenterology & Hepatology
- Published
- 2023-03-17
- Volume
- 20
- Issue
- 8
- Pages
- 487-503
- ISSN
- 1759-5045 (ISSN-L)
- 1759-5053
- PMC
- PMC12165718
- OpenAlex
- W4327744345
- Cited by
- 354
- References
- 224
- Citations by year
- 2026: 70 · 2025: 127 · 2024: 120 · 2023: 37
- FWCI
- 15.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Reviews Gastroenterology & Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- Fundació Institut de Recerca Hospital Universitari Vall d’Hebron
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK128289)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Keywords
- nonalcoholic steatohepatitis, hepatocellular carcinoma, non-alcoholic fatty liver disease, tumor immune microenvironment, gut microbiota, obesity, diabetes mellitus, metabolic syndrome, immune checkpoint inhibitors, anti-angiogenic therapy, locoregional therapy, surgical resection, cancer surveillance, biomarkers, immune evasion
- MeSH terms
- Immune Checkpoint Inhibitors, Diabetes Mellitus, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Obesity, Disease Progression, Tumor Microenvironment, Non-alcoholic Fatty Liver Disease
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