MASLD, MASH, and MetALD: Integrated Mechanisms, Diagnostics, and Therapeutic Strategies for Metabolic and Alcohol-Associated Liver Disease

Metabolic liver diseases, especially metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), are now among the most prevalent chronic liver conditions worldwide and are major drivers of cirrhosis and hepatocellular carcinoma (HCC). In parallel, a substantial proportion of individuals with metabolic dysfunction report alcohol consumption that is clinically meaningful, and in many cases even moderate intake is sufficient to influence disease progression. This has drawn attention to a blended phenotype in which metabolic risk and alcohol exposure synergize to exacerbate hepatocellular injury, inflammation, and fibrosis. This overlapping entity, termed metabolic dysfunction and alcohol-associated liver disease (MetALD), was introduced within the steatotic liver disease framework to better reflect real-world biology and prognosis and to address the limitations of an exclusion-based diagnosis. However, MetALD still lacks fully validated diagnostic thresholds, and its precise phenotyping remains an active area of debate. Key unmet needs remain: (i) how to distinguish MASLD/MASH from MetALD in routine care; (ii) how alcohol exposure patterns and metabolic burden jointly shape disease trajectory; (iii) which biomarkers and non-invasive tests best predict fibrosis progression and clinical outcomes; (iv) how to tailor therapy when both metabolic drivers and alcohol use contribute to disease; (v) how to identify mechanistic biomarkers that differentiate predominantly metabolic from alcohol-related injury, including markers such as phosphatidylethanol and metabolomic signatures; and (vi) how to develop integrated algorithms that combine metabolic risk, alcohol use, fibrosis stage, and genetic susceptibility for more precise stratification and management. This Research Topic aims to integrate mechanistic, translational, and clinical evidence that advances the understanding and management of MASLD/MASH and MetALD. We seek submissions that clarify causal pathways and inter-organ drivers, improve non-invasive risk stratification, and evaluate therapeutic strategies spanning lifestyle intervention, pharmacotherapy, metabolic bariatric surgery, and other personalized approaches. We welcome Original Research, Review, Mini-Review, Case Report, and Perspective articles covering (but not limited to): • Addressing the heterogeneity of MASLD/MASH and MetALD, and developing molecular classifications to guide clinical practice. • Definitions and phenotyping of MASLD/MASH and MetALD, including alcohol quantification, drinking patterns, longitudinal reassessment, and unresolved diagnostic thresholds. • Pathogenesis, including insulin resistance; the adipose–liver and gut–liver axes; bile acids; hepatokines/adipokines; immune remodeling; and fibrogenesis. • Alcohol–metabolic synergy, including lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, oxidative stress, ferroptosis/pyroptosis, and microbiome-mediated mechanisms. • Biomarkers and non-invasive diagnostics, including FIB-4 and elastography-based pathways (VCTE/MRE), imaging biomarkers, and multi-omics approaches such as lipidomics, proteomics, and metabolomics. • Mechanistic biomarkers that differentiate metabolic versus alcohol-related liver injury, including phosphatidylethanol, alcohol-related metabolomic signatures, and other pathway-informed biomarkers. • Genetics and causal inference, including GWAS, rare variants, Mendelian randomization, and gene–environment interactions. • Clinical outcomes, including fibrosis progression, portal hypertension, HCC risk, and cardiometabolic multimorbidity. • Integrated risk algorithms combining metabolic risk factors, alcohol exposure, fibrosis stage, and genetic information to improve diagnosis, prognostication, and treatment selection. • Therapeutics, including lifestyle and dietary intervention, incretin-based therapies, FXR/PPAR pathways, anti-fibrotic strategies, and integrated models addressing both alcohol use and metabolic risk, as well as clinical trial and real-world evidence. • Holistic patient management strategies derived from real-world evidence or expert opinion. Topic editors: Lanlan Chen, Hanyang Liu, Nan Ma Source: https://www.frontiersin.org/research-topics/79086/masld-mash-and-metald-integrated-mechanisms-diagnostics-and-therapeutic-strategies-for-metabolic-and-alcohol-associated-liver-disease