Metabolic dysfunction-associated steatotic liver disease: pathogenesis and novel treatment options

Metabolic dysfunction-associated steatotic liver disease (MASLD), the recently introduced terminology superseding non-alcoholic fatty liver disease (NAFLD), has emerged as the most prevalent chronic liver condition globally. This multisystem disorder, driven by systemic insulin resistance (IR) and metabolic dysregulation, not only progresses to cirrhosis and hepatocellular carcinoma (HCC) but also substantially increases the risk of cardiovascular disease (CVD), type 2 diabetes (T2D), and extrahepatic malignancies. Despite the recent FDA approval of resmetirom for a subset of patients with advanced fibrosis, effective pharmacological therapies for the broad MASLD population remain a critical unmet need, underscoring the urgency of continued research into disease mechanisms and therapeutic targets. This review synthesizes recent advances in three interconnected domains: the complex pathogenesis of MASLD (including lipotoxicity, mitochondrial dysfunction, inflammation, and fibrogenesis), the evolving landscape of non-invasive diagnostic tools, and the development of novel therapeutic agents targeting key pathways. By critically analyzing both successful late-stage trials and instructive failures, we highlight the challenges of translating mechanistic insights into clinically meaningful outcomes. By providing a comprehensive, integrated overview of current knowledge and future directions, this review aims to serve as a valuable resource for researchers and clinicians working toward effective, personalized interventions for this global health challenge.