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. 2026 Mar 23;19:583883. doi: 10.2147/OTT.S583883

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© 2026 Xu and Gao.

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).

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Schematic overview of the dual regulatory role of SIK2 in lipid synthesis and fatty acid oxidation in ovarian cancer. SIK2 orchestrates lipid metabolic reprogramming via two distinct axes: (1) The lipogenesis axis: SIK2 activates the PI3K/AKT/mTOR pathway to upregulate SREBP1c and SREBP2, which further drive the expression of FASN and HMGCR to promote de novo fatty acid synthesis and cholesterol synthesis, respectively; (2) The fatty acid oxidation axis: In the adipocyte-rich tumor microenvironment, adipocyte-released free fatty acids activate the PLC signaling pathway, which induces SIK2 autophosphorylation at Ser358. Activated SIK2 phosphorylates ACC to reduce its activity, which relieves the inhibitory effect of malonyl coenzyme A on CPT1A, ultimately enhancing fatty acid oxidation to supply energy for ovarian cancer cells in metastatic niches.

Abbreviations: SIK2, Salt-inducible kinase 2; PI3K, Phosphoinositide 3-kinase; SREBP, Sterol regulatory element-binding protein; FASN, Fatty acid synthase; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; PLC, Phospholipase C; Ser358, Serine 358; ACC, Acetyl-CoA carboxylase; CPT1A, Carnitine palmitoyltransferase 1A.