Liver kinase B1–adenosine monophosphate-activated protein kinase pathway (LKB1–AMPK pathway) (LKB1–AMPK pathway)

The Liver kinase B1–adenosine monophosphate-activated protein kinase (LKB1–AMPK) pathway is a central metabolic signaling axis that couples cellular energy status to growth, survival, and polarity [2, 8, 9]. At its core, the serine/threonine kinase LKB1 (encoded by the STK11 gene) acts as the primary upstream activator of AMPK, phosphorylating it at the Thr172 residue in response to an increased AMP:ATP ratio or metabolic stress [10, 12, 13]. Once activated, AMPK functions as a master metabolic switch, inhibiting energy-consuming anabolic processes—such as lipid and protein synthesis via the suppression of the mTORC1 pathway—while stimulating energy-producing catabolic pathways like glucose uptake and fatty acid oxidation [2, 10, 12]. This pathway is a major therapeutic target in metabolic diseases, most notably through the drug metformin, which activates the axis to suppress hepatic gluconeogenesis and improve insulin sensitivity [7, 11]. Beyond its role in metabolism, the LKB1–AMPK pathway functions as a potent tumor suppressor; its inactivation via STK11 mutations is the underlying cause of Peutz-Jeghers syndrome and is frequently observed in sporadic cancers such as non-small cell lung cancer [1, 3, 14]. Therapeutic strategies currently focus on either restoring pathway activity in deficient tumors or exploiting the unique metabolic vulnerabilities created by its loss [3, 5, 9].

Other names

STK11-AMPK axisLKB1-AMPK signaling pathwayPeutz-Jeghers syndrome kinase pathway

Activation of AMPK via LKB1-mediated phosphorylation at Thr172; inhibition of the mTORC1 complex; suppression of hepatic gluconeogenesis; stimulation of glucose uptake and fatty acid oxidation; induction of cell cycle arrest through p53 and p21 activation.