Hepatocellular carcinoma (HCC) represents the most common primary malignancy of the liver and remains a leading cause of cancer-related mortality worldwide. In recent years, the epidemiological landscape of HCC has been profoundly influenced by the rising prevalence of metabolic dysfunction–associated steatotic liver disease (MASLD), a condition formerly known as non-alcoholic fatty liver disease (NAFLD). The close interplay between metabolic disorders, chronic inflammation, immunometabolism, and hepatic carcinogenesis, often modulated by the microbiome–liver axis, has drawn increasing attention from both basic scientists and clinicians.

From laboratory investigations uncovering the molecular pathways of lipo-toxicity, with oxidative stress, immune dysregulation, with chronic inflammation, and crucial aspects of metabolic reprogramming, to clinical studies identifying biomarkers and therapeutic targets, the understanding of the MASLD–HCC axis has expanded significantly. This translational journey from bench to bedside highlights the importance of integrating experimental insights with clinical evidence to improve risk stratification, early detection, and management strategies for patients at risk of HCC in the context of metabolic liver disease.

The main goal of this Research Topic is to bridge the gap between basic scientific discoveries and their clinical applications in the context of patient’s population with HCC and MASLD to better understand pathways and risks of the unfavorable clinical outcome.

The topics of interest and to focus of this collection, must be to:

1. Elucidate molecular mechanisms underlying the progression from MASLD to HCC, focusing on metabolic, inflammatory, and genetic pathways, including the roles of immunometabolism, the microbiome–liver axis, and metabolic reprogramming identified in experimental models.

2. Integrate translational research by validating laboratory findings in clinical cohorts, aiming to identify reliable biomarkers for early diagnosis and disease stratification, particularly those linked to immunometabolism, microbiome alterations, or metabolic reprogramming.

3. Assess prognostic and therapeutic implications of emerging molecular targets, exploring their potential role in personalized treatment approaches, especially those related to modulating immunometabolic pathways, the gut-liver axis, or aberrant metabolic reprogramming.

4. Establish a link between bench and bedside, fostering collaboration among basic researchers, clinicians, and data scientists to accelerate the translation of discoveries into clinical practice, with a particular emphasis on how immunometabolism, the microbiome, and metabolic reprogramming impact patient care.

5. Generate evidence-based clinical insights that may improve patient outcomes through earlier detection, better risk assessment, and innovative therapeutic strategies, by leveraging new understandings of immunometabolism, the microbiome–liver axis, and metabolic reprogramming.

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Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Hepatocellular Carcinoma (HCC): From Laboratory Insights to Clinical Evidence