Figure 1.

Schematic overview of the molecular mechanisms by which SIK2 regulates the Warburg effect and glucose metabolic reprogramming in ovarian cancer cells. SIK2 drives glycolytic enhancement and mitochondrial dysfunction via two parallel pathways: (1) SIK2 activates the PI3K/AKT/mTOR signaling axis, which upregulates HIF-1α and its downstream glycolytic enzymes HK2 and PFKL, ultimately promoting glucose uptake and lactate production to enhance glycolysis; (2) SIK2 directly phosphorylates the mitochondrial fission protein Drp1 at Ser616, which induces excessive mitochondrial fission, impairs mitochondrial respiratory function, and inhibits oxidative phosphorylation. These two pathways synergistically reinforce the Warburg effect to support the rapid proliferation of ovarian cancer cells.

Abbreviations: SIK2, Salt-inducible kinase 2; PI3K, phosphoinositide 3-kinase; HIF-1α, hypoxia-inducible factor 1α; HK2, hexokinase 2; PFKL, phosphofructokinase; Drp1, dynamin-related protein 1; Ser616, serine 616.