ABSTRACT 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.
Choi et al. (Thu,) studied this question.
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