The LKB1-AMPK pathway in NAFLD: molecular mechanisms and therapeutic implications.

Abstract

The LKB1-AMPK signaling pathway is a central regulator of hepatic energy homeostasis and is increasingly implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). LKB1-mediated AMPK activation promotes fatty acid β-oxidation, autophagy, and mitochondrial biogenesis. At the same time, it suppresses de novo lipogenesis, cholesterol synthesis, and mTOR-dependent anabolic growth, thereby supporting hepatic lipid and energy balance. Impairment of this pathway may disrupt hepatic lipid homeostasis and promote triglyceride accumulation. Oxidative stress, microRNA dysregulation, hormonal imbalance, copper dysregulation, and inflammatory mediators can further contribute to mitochondrial injury, hepatocellular apoptosis, and inflammatory activation. These processes may facilitate progression from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocarcinogenesis. LKB1-AMPK signaling also intersects with immunometabolic and stromal pathways. Defects in hepatic immune and stromal compartments may enhance pro-inflammatory Th17 responses and fibrogenic transformation. Therapeutically, pharmacologic activation of LKB1-AMPK has shown context-dependent cytoprotective potential, mainly in preclinical models. Natural compounds, synthetic small molecules, repurposed agents, and nutrient-derived modulators can activate LKB1-AMPK signaling. These interventions reduce steatosis, oxidative stress, and endoplasmic reticulum stress while enhancing autophagic flux and fatty acid catabolism. Additional benefits may arise through gut microbiota-mediated signaling that converges on LKB1-AMPK-dependent metabolic restoration. Overall, the LKB1-AMPK axis links nutrient sensing, mitochondrial function, redox control, and inflammatory regulation in NAFLD pathophysiology. Current evidence supports further development of pathway-targeted interventions, but clinical translation requires stronger human validation.