Beyond Weight Loss: Tirzepatide as a Metabolic Disease-Modifying Strategy for Metabolic Dysfunction-Associated Steatohepatitis: A Narrative Review.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver disease worldwide and a major contributor to liver-related morbidity and mortality. Its progressive subtype, metabolic dysfunction-associated steatohepatitis (MASH), is characterized by hepatocellular injury, inflammation, and fibrosis, which may ultimately progress to cirrhosis and hepatocellular carcinoma. Despite the rapidly increasing global burden of MASH, effective pharmacological therapies remain limited. Lifestyle modification remains the cornerstone of management; however, achieving and maintaining the degree of sustained weight loss required for meaningful histological improvement is challenging in routine clinical practice. OBJECTIVE: This perspective review evaluates the emerging therapeutic potential of tirzepatide in the management of MASH. METHODS: Relevant mechanistic studies, clinical trials, and recent literature published between 2015 and 2025 were reviewed to evaluate the emerging role of tirzepatide and incretin-based therapies in metabolic liver disease. RESULTS: Tirzepatide is a first-in-class dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist that produces substantial metabolic benefits, including improved glycemic control, enhanced insulin sensitivity, and significant weight reduction. These effects directly address key drivers of MASLD and MASH, including hepatic lipid accumulation, insulin resistance, and systemic inflammation. Emerging clinical evidence, particularly from the SYNERGY-NASH trial, suggests that tirzepatide may promote resolution of steatohepatitis and improvement in fibrosis in patients with biopsy-confirmed MASH. CONCLUSION: Tirzepatide represents a promising metabolic disease-modifying therapy for MASH. Nevertheless, larger and longer-term clinical studies are needed to establish its durability of benefit, long-term safety, and optimal role within evolving treatment strategies for metabolic liver disease.