Convergent Metabolic Pathways in MASH Therapeutics: An AMPK-Centric Analysis

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver-related morbidity driven by systemic metabolic dysregulation. The recent approval of resmetirom and the clinical success of GLP-1 receptor agonists have heralded a new era in MASH therapy, yet a convergent understanding of the complex mechanisms of these diverse agents is lacking. This review proposes a mechanistic framework centred on the convergent signalling of AMP-activated protein kinase (AMPK), a master regulator of hepatic energy homeostasis. We examine key metabolism-based therapeutics-pioglitazone, GLP-1 receptor agonists, SGLT2 inhibitors, resmetirom and statins-to delineate how distinct upstream triggers converge on AMPK. Synthesising the latest evidence, we clearly delineate how each drug class activates AMPK either indirectly-through systemic effects like weight loss and glycemic control-or via direct actions on hepatocytes. We specifically contrast the liver-targeted action of resmetirom with the predominantly systemic effects of semaglutide and discuss the 'epigenetic lock-in' hypothesis, wherein chronic metabolic stress perpetuates the disease state. Based on this framework, we propose rational strategies for combination therapy. In conclusion, this AMPK-centric framework provides a novel lens for understanding the complex pharmacology of MASH drugs and offers a valuable clinical roadmap for personalising treatment strategies to individual patient phenotypes.