Fig. 1

AMPK activation pathways and their regulatory effects on various metabolic processes. AMPK is activated via canonical (AMP/ADP-dependent) and non-canonical (AMP/ADP-independent) pathways. In canonical pathways, AMPK is activated in response to increased levels of AMP or ADP, and the upstream kinase LKB1 phosphorylates AMPK upon activation. AMP/ADP can directly activate AMPK through conformational modification and inhibit PP2A/C-mediated dephosphorylation of AMPK. In non-canonical pathways, AMPK is activated through other mechanisms instead of responding to an increase in AMP/ADP levels. AMPK can respond to an increase in Ca²⁺ levels and is phosphorylated by the upstream kinase CaMKKβ. Under lysosomal damage, the upstream kinase TAK1 activates AMPK. Under glucose starvation, the lysosomal adapter protein AXIN1 or AXIN2 binds to LKB1, leading to the phosphorylation of AMPK. In addition, AMPK can be activated by glycogen, DNA damage agents and AMPK activators. Upon activation, AMPK inhibits ATP-consuming biosynthetic pathways, such as mTOR, ACC1/SREBP1C/HMGCR and TIF-1 A pathways and glycogen synthesis, to inhibit protein synthesis, lipogenesis, glycogen synthesis and rRNA synthesis. In addition, AMPK activates the catabolic pathways that produce ATP, such as ACC2, ULK1, GLUT4 and PGC-1α/SIRT1, to enhance fatty acid oxidation, autophagy, glycolysis and mitochondrial biogenesis. Under normal circumstances, inositol inhibits AMPK activation by binding to AMPK subunits. High glucose and ATP competitive AMPK inhibitor compound C can also inhibit the activity of AMPK. The red arrow is meant to activate. The green arrow is meant to inhibit

LKB1 liver kinase B1, PP2A/C protein phosphatase 2 A/C, CaMKKβ calmodulin-dependent protein kinase kinase-β, TAK1 transforming growth factor kinase 1, AXIN1 axis inhibition protein 1, SREBP1 sterol regulatory element-binding protein 1, HMGCR HMG-CoA reductase, ACC1 acetyl coenzyme A carboxylase 1, TIF-1 A transcriptional intermediary factor 1 A, mTOR mammalian target of rapamycin, PGC-1 peroxisome proliferator-activated receptor-gamma coactivator, ULK1 UNC-51-like kinase 1, GLUT4 glucose transporter 4, SIRT1 sirtuin 1