AMPK-Directed Therapeutics for MASLD: Mechanistic Rationale, Activator Classes, and Clinical Translation.

Metabolic-associated steatotic liver disease (MASLD) affects an estimated 25-30% of the global adult population and represents a leading cause of liver-related morbidity. However, approved pharmacological therapies remain strictly limited. AMP-activated protein kinase (AMPK), a highly conserved heterotrimeric serine/threonine kinase and major regulator of cellular energy homeostasis, is chronically suppressed in the steatotic liver through hyperinsulinemia, ceramide signaling, oxidative stress, and epigenetic silencing of its upstream activator LKB1. This suppression removes a critical brake on de novo lipogenesis while simultaneously impairing fatty acid β-oxidation, mitochondrial quality control, anti-inflammatory signaling, and hepatic stellate cell quiescence. Thus, AMPK restoration may serve as an effective strategy capable of addressing multiple pathological drivers of MASLD. This review examines the molecular architecture of the AMPK heterotrimer, the downstream signaling networks governing hepatic lipid metabolism, glucose homeostasis, and fibrogenesis, and a spectrum of AMPK-activating pharmacology relevant to MASLD. Furthermore, it would introduce indirect activators including metformin, berberine, resveratrol, and related phytochemicals, as well as direct allosteric activators targeting the ADaM site, such as A-769662, PF-06409577, MK-8722, Compound 991, and the clinical-stage compound O304. Translational challenges confronting this therapeutic class are critically evaluated.