genomics

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disorder globally, affecting over 30% of adults. It is increasingly recognized as a multisystem disease with significant cardiometabolic and oncologic consequences. Recent advances between 2021 and 2025 have substantially transformed its conceptual understanding, diagnosis, and clinical management. Objective: This review aims to critically evaluate global progress in NAFLD research and management from 2021 to 2025, with emphasis on epidemiology, pathophysiology, diagnostic innovations, therapeutic developments, and the emergence of precision hepatology, while addressing the transition toward metabolic dysfunction-associated fatty liver disease (MAFLD). Methods: A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science databases, covering studies published between June 2021 and December 2025. Relevant clinical trials, guidelines, and high-impact research articles were systematically analyzed across key domains including epidemiology, molecular mechanisms, diagnostics, therapeutics, and public health strategies. Results: The global prevalence of NAFLD has increased across diverse populations, including pediatric, elderly, lean, and socioeconomically disadvantaged groups. The MAFLD terminology has gained traction for better reflecting metabolic dysfunction, although debates persist. Mechanistic insights highlight the roles of insulin resistance, lipotoxicity, mitochondrial dysfunction, impaired autophagy, and gut microbiota dysbiosis. Advances in genomics and epigenetics have identified key variants such as PNPLA3 and TM6SF2, along with circulating biomarkers including miR-122 and Pro-C3. Non-invasive diagnostic tools, particularly imaging modalities and artificial intelligence-based systems, are increasingly replacing liver biopsy. Although no pharmacological therapy has yet received full regulatory approval, several agents, including obeticholic acid, resmetirom, lanifibranor, and semaglutide, are in advanced stages of clinical development. Lifestyle modification remains the cornerstone of management. NAFLD is strongly associated with increased risk of cardiovascular disease, type 2 diabetes, chronic kidney disease, and malignancies. Emerging precision hepatology approaches integrating multi-omics, artificial intelligence, and digital health technologies are enabling personalized disease management. Conclusion: NAFLD is evolving from a liver-specific disorder into a global multisystem health challenge. Despite significant advances, key challenges remain in standardizing diagnostic criteria, ensuring equitable access to therapies, and addressing global health disparities. The integration of precision medicine, digital technologies, and public health strategies holds promise for reducing the burden of NAFLD in the coming decade.