CDKL3 (cyclin-dependent kinase-like 3) is a serine/threonine kinase that plays critical roles in cell cycle regulation, cancer progression, and metabolic disease 1. The protein primarily functions in the nucleus where it associates with cyclins to directly phosphorylate retinoblastoma (Rb) protein for cell cycle progression and prevents CDK4 degradation by phosphorylating CDK4 at T172, sustaining G1 phase advancement 1. In metabolic regulation, CDKL3 serves as a guardian against metabolic dysfunction-associated steatotic liver disease (MASLD) by directly phosphorylating FoxO1 at unconventional sites, leading to its ubiquitination-dependent degradation and preventing lipid accumulation 2. CDKL3 is significantly upregulated in multiple cancers including hepatocellular carcinoma, prostate cancer, and triple-negative breast cancer, where it promotes tumor progression through various mechanisms including p53 pathway inhibition and STAT1 regulation 345. In clear cell renal carcinoma, CDKL3 functions as a cytosolic adaptor protein that potentiates mTORC2-dependent Akt activation independently of its kinase activity 6. Additionally, CDKL3 regulates ciliary structure by controlling proximal segment length through intraflagellar transport mechanisms 7. The development of specific CDKL3 inhibitors shows therapeutic promise for cancer treatment 1.