Metabolic Dysfunction‐Associated Steatotic Liver Disease ( <scp>MASLD</scp> ): Mechanisms, Clinical Implications and Therapeutic Advances
D.A. Miller, Kiana F. McCauley, Kimberly J. Dunham‐Snary
Abstract
INTRODUCTION: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has emerged as the most prevalent chronic liver disease worldwide, affecting ~25%-30% of the adult population, with higher prevalence observed in individuals with obesity and type 2 diabetes. Among reported MASLD cases, prevalence is consistently higher in men than in women, and global incidence has risen by ~50% over the past two decades, mirroring the global rise in obesity and metabolic syndrome. MASLD encompasses a spectrum of hepatic pathologies ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Despite its high prevalence, the heterogeneity in disease progression and relative absence of approved pharmacological therapies pose challenges for effective clinical management. METHODS AND RESULTS: This review synthesises current literature on MASLD across epidemiology, pathophysiology, clinical presentation and treatment. Key molecular mechanisms, including lipid metabolism dysregulation, insulin resistance and mitochondrial dysfunction, are examined with a focus on understanding the basis for progression to metabolic dysfunction-associated steatohepatitis (MASH). Clinical manifestations, diagnostic tools and risk stratification systems for MASLD are summarised. Current and emerging therapies such as lifestyle interventions, pharmacological agents and microbiome-targeted strategies are reviewed. The review also highlights ongoing challenges, including diagnostic limitations, disease heterogeneity and disparities in care. CONCLUSION: MASLD is a complex, multifactorial liver disease with a growing public health impact, driven by the rising prevalence of metabolic syndrome. Mitochondrial dysfunction is a critical nexus linking genetic susceptibility to metabolic stress and inflammatory responses. Preclinical models that capture these mitochondrial contributions are vital for therapeutic discovery and for advancing personalised medicine approaches in MASLD care.