The MASLD–MASH–HCC Axis: Metabolic, Genetic, and Histopathological Insights

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. In recent years, the global epidemiology of HCC has been profoundly reshaped by the rising prevalence of metabolic liver diseases. Metabolic Associated Steatotic Liver Disease (MASLD) and its progressive form, Metabolic Associated Steatohepatitis (MASH), have emerged as major drivers of hepatocarcinogenesis, surpassing viral hepatitis in several regions. These conditions induce profound alterations in hepatic metabolism, architecture, and cellular homeostasis, generating a permissive environment for malignant transformation.

The interplay between metabolic dysfunction, chronic inflammation, oxidative stress, and fibrotic remodeling contributes to a unique histopathological spectrum of MASLD-related HCC, often characterized by distinct architectural and cellular features. In parallel, molecular and epigenetic reprogramming—including deregulated lipid and glucose metabolism, altered gene expression, and chromatin modifications—further accelerates tumor initiation and progression.

Despite these advances, the precise mechanisms linking MASLD/MASH to HCC remain incompletely understood, and reliable biomarkers for early detection are still lacking. A deeper integration of metabolic, genetic, and anatomo-pathological perspectives is urgently needed to improve risk stratification, diagnosis, and therapeutic strategies.

This Research Topic aims to provide a comprehensive overview of the MASLD–MASH–HCC axis, highlighting the molecular, metabolic, and histopathological mechanisms that underlie hepatocarcinogenesis in metabolic liver disease. By bringing together contributions from basic, translational, and clinical research, we seek to clarify how metabolic dysfunction and epigenetic reprogramming drive malignant transformation and how these processes can be targeted for prevention and therapy.

The ultimate goal is to bridge the gap between experimental findings and clinical practice, fostering the identification of novel biomarkers, molecular pathways, and therapeutic targets. This collection will serve as a platform to stimulate collaboration across disciplines and advance our understanding of HCC pathogenesis in the context of metabolic liver disease.

We welcome original research, reviews, and perspectives addressing the following themes:
• Metabolic dysfunction and hepatocarcinogenesis: lipid/glucose metabolism, oxidative stress, mitochondrial dysfunction.
• Histopathological spectrum of MASLD/MASH-related HCC: architectural and cellular features, fibrosis, and microenvironmental remodeling.
• Molecular and epigenetic reprogramming: gene expression, chromatin modifications, non-coding RNAs.
• Biomarkers and risk stratification: novel diagnostic tools, prognostic indicators, and early detection strategies.
• Therapeutic targets and interventions: metabolic modulators, immunotherapy, and combined approaches.
• Translational and clinical perspectives: integration of basic science with patient cohorts and clinical outcomes.

Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal.

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This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Metabolic Associated Steatotic Liver Disease (MASLD); Metabolic Associated Steatohepatitis (MASH); Hepatocellular carcinoma (HCC); Epigenetic reprogramming; Biomarkers and therapeutic targets

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.