Next-Generation Therapies for MASH and Metabolic Liver Disease

The rapidly evolving landscape of metabolic liver disease research reflects a much deeper understanding of its systemic complexity. The redefinition of NAFLD/NASH under the MASLD/MASH framework recognizes that hepatic steatosis is not an isolated hepatic condition but a multifactorial metabolic disorder intertwined with endocrine, immunologic, and gut-derived mechanisms. Although recent regulatory achievements have marked an important milestone in MASH pharmacotherapy, substantial unmet needs persist, particularly in reversing advanced fibrosis, mitigating inflammation, and achieving durable metabolic resolution across diverse patient populations. These limitations underline the necessity for innovative research directions that integrate combination therapies, biomarkers guiding therapeutic decisions, and real-world validation of efficacy and safety beyond clinical trial populations.

This Research Topic aims to bring together cutting-edge contributions that define the next phase of therapeutic innovation in MASH and metabolic liver disease. Future progress lies in precision medicine approaches combining metabolic, genetic, and transcriptomic profiling to identify patient subgroups most likely to respond to specific interventions. Increasing attention is being directed toward nucleic acid-based therapeutics—including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA)—that selectively modulate gene expression linked to lipid metabolism, inflammation, and fibrosis. By showcasing advancements in multi-modal treatments, dual and triple agonists, and microbiome-targeted or immune-modulating therapies, this Research Topic seeks to outline how new molecular mechanisms, predictive biomarkers, and real-world outcome studies will shape clinical translation. In doing so, it fosters a multidimensional view of hepatometabolic health, aligning bench discoveries with personalized treatment pathways and scalable implementation strategies.

We welcome original research, reviews, and clinical trial protocols that address, but are not limited to, the following themes:

- Combination and Modular Therapies: Integration of small molecules, biologics, ASOs, and siRNA for synergistic targeting of metabolic, inflammatory, and fibrotic pathways.
- Precision Medicine and Patient Stratification: Molecular and metabolic profiling approaches to guide individualized therapeutic strategies and optimize treatment response.
- Predictive and Dynamic Biomarkers: Discovery and validation of biomarkers that predict therapeutic efficacy, fibrosis regression, and long-term liver outcomes.
- Real-World Implementation: Post-approval evaluation and longitudinal monitoring of newly approved treatments, including cost-effectiveness and patient-reported outcomes.
- Nucleic Acid-Based Therapeutics: Development and clinical application of ASO and siRNA technologies targeting key hepatocellular and metabolic pathways.
- Gut-Liver Axis Modulators: Leveraging the microbiome through engineered probiotics, postbiotics, and bile acid modulators to restore immune and metabolic homeostasis.
- Anti-Fibrotic and Metabolic Interventions: Novel strategies, such as metabolic surgery, regenerative therapies, and anti-fibrotic biologics aimed at reversing cirrhosis and preventing hepatocellular carcinoma (HCC).

Article types and fees

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

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Community Case Study
• Curriculum, Instruction, and Pedagogy
• Data Report
• Editorial
• FAIR² Data
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

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

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Community Case Study
• Curriculum, Instruction, and Pedagogy
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Policy and Practice Reviews
• Policy Brief
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: MASH, MASLD, Clinical Translation, Anti-fibrotic Therapies, Gut-Liver Axis, Small Molecules, Biologics, Lipid Metabolism, Metabolic Inflammation

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.