Genetic determinants of steatotic liver disease
Yang et al. emphasise that genetic architecture strongly modulates susceptibility to SLD. Genome-wide association studies have revealed several critical variants: (1) PNPLA3 (I148M, rs738409): the strongest risk allele linked to lipid droplet metabolism dysfunction in hepatocytes and stellate cells, promoting steatosis, fibrosis, and HCC; (2) TM6SF2 (E167K, rs58542926): impairs very-low-density lipoprotein (VLDL) secretion, leading to triglyceride retention; (3) MBOAT7 (rs641738): alters phospholipid remodelling and predisposes to hepatic lipid accumulation; (4) HSD17B13 (rs72613567): confers a protective effect, reducing steatosis and inflammation. These variants integrate with environmental influences—obesity, insulin resistance, and sedentary lifestyle—creating a synergistic milieu for hepatic injury.
Cellular crosstalk in disease progression
A hallmark of MASLD progression is hepatocellular injury triggering immune activation. Damaged hepatocytes release damage-associated molecular patterns (DAMPs), reactive oxygen species (ROS), and extracellular vesicles (EVs), initiating inflammation. Kupffer cells and monocyte-derived macrophages amplify injury through cytokine secretion, while neutrophils contribute both pro-inflammatory and pro-resolving signals. Hepatic stellate cells (HSCs) serve as central effectors of fibrosis. Their activation is driven by IL-6–STAT3, YAP/TAZ, and TGF-β pathways. Transcription factors such as JUNB and RUNX1/2 orchestrate lineage-specific activation signatures, while sirtuin 6 suppresses HSC activation by deacetylating YAP/TAZ. Importantly, osteopontin secreted by hepatocytes under metabolic stress promotes fibrogenesis—providing a link between metabolic dysfunction and stromal activation.
Alcohol-associated liver disease (ALD): shared yet distinct mechanisms
Although metabolic and alcohol-induced liver diseases share common pathways, ALD uniquely involves acetaldehyde toxicity and oxidative stress. Genetic susceptibility overlaps substantially—PNPLA3, TM6SF2, and HSD17B13 variants recur as modulators of risk. The review notes that alcohol also disrupts gut-liver axis homeostasis, reducing vitamin B6 synthesis and impairing glutathione metabolism, thereby enhancing oxidative stress.
Neutrophil infiltration, a histological hallmark of alcohol-associated hepatitis (AH), is driven by IL-8/CXCL8 signalling. Targeting neutrophil recruitment and activation (via CXCR1/2 blockade) emerges as a potential therapeutic approach. The authors highlight the dual role of neutrophils in promoting injury yet facilitating resolution through macrophage modulation and hepatocyte regeneration.
From steatosis to cancer: mechanistic continuum
The transition from chronic steatotic injury to HCC is mediated by cumulative genomic instability, fibrotic remodelling, and immune dysregulation. Notably, the aetiological landscape of HCC has shifted—viral hepatitis is declining, whereas metabolic and alcohol-related cancers are surging.
Distinct molecular signatures differentiate MASH-related HCC from other subtypes. MASH-HCC exhibits higher mutation rates in ACVR2A, TERT, and CTNNB1, whereas ALD-HCC frequently harbours TP53 and ARID1A mutations. The tumor immune microenvironment in MASH-HCC is characterised by reduced macrophage and NK cell infiltration, implying impaired immune surveillance.
Preclinical studies further reveal that PNPLA3 I148M variants promote HCC formation under alcohol or metabolic stress. Crosstalk between hepatocytes and tumour cells via YAP-related EVs enhances metastatic potential, while bile acid imbalance contributes to T-cell exhaustion through oxidative and endoplasmic reticulum stress.
Emerging therapeutic strategies
Yang and colleagues provide an extensive overview of novel therapeutics reshaping SLD management: (1) Thyroid hormone receptor-β (THR-β) agonists: Resmetirom, the first FDA-approved drug for MASH (2024), improves fibrosis in ~25% of patients without worsening steatosis, validating thyroid signalling as a metabolic target. (2) GLP-1–based poly-agonists: Dual and triple incretin receptor agonists—tirzepatide (GLP1R/GIPR) and retatrutide (GLP1R/GIPR/GCGR)—produce profound reductions in hepatic fat (up to 80%) and histological resolution of MASH in up to 62% of patients. (3) FGF21 analogues:
Agents such as pegozafermin and efruxifermin improve liver stiffness and fibrosis by enhancing mitochondrial function and lipid oxidation. (4) FXR agonists and BA modulators: Cilofexor and obeticholic acid target bile acid homeostasis, reducing inflammation and fibrosis. Aldafermin (FGF19 analogue) improves histological fibrosis in MASH with cirrhosis.
Liver cancer therapy: expanding horizons
For advanced HCC, the therapeutic landscape now includes immunotherapy-based combinations. Adjuvant atezolizumab plus bevacizumab significantly prolongs recurrence-free survival post-resection, while first-line regimens such as durvalumab plus tremelimumab (STRIDE) and sintilimab plus bevacizumab biosimilar (ORIENT-32) demonstrate superior overall survival compared with sorafenib across viral and non-viral aetiologies.
Preventive and translational perspectives
The authors underscore that the heterogeneity of SLD-related cancer necessitates personalised strategies integrating genetic, metabolic, and immune profiling. Preventive measures—weight control, reduced alcohol intake, and diabetes management—remain the foundation of disease mitigation. However, molecularly targeted interventions are now poised to transform outcomes.
In conclusion, this landmark review provides an integrative framework linking steatotic liver disease, fibrosis, and carcinogenesis. As the global burden of metabolic liver disease escalates, these insights highlight a translational roadmap from understanding pathogenesis to developing curative interventions.
See the article:
Yang Z, Liu Z, Liu W, et al. Steatotic liver disease and cancer: from pathogenesis to therapeutic targets. eGastroenterology 2025;3:e100218. doi:10.1136/egastro-2025-100218
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