MASTL (microtubule associated serine/threonine kinase like) is a serine/threonine kinase that functions as a master regulator of mitotic progression. Its primary function involves promoting M phase entry and maintenance by inactivating protein phosphatase 2A (PP2A) through phosphorylation of ARPP19 and ENSA at specific serine residues, which keeps cyclin-B1-CDK1 activity elevated 1. MASTL localizes to the nucleus during interphase and relocalizes to centrosomes during mitosis 2. Mechanistically, MASTL enables proper chromosome 10, anaphase progression, and cytokinesis by sustaining mitotic phospho-protein phosphorylation states 2. During mitotic exit, PP1 dephosphorylates and deactivates MASTL, triggering phosphatase reactivation through a feedback mechanism 3. Beyond cell-cycle regulation, MASTL exhibits kinase-independent functions regulating the actomyosin cytoskeleton 4. Clinically, MASTL is significantly upregulated across multiple cancer types including hepatocellular carcinoma, breast cancer, and gastric cancer, correlating with aggressive features and poor prognosis 5 6 7. In HCC, MASTL drives lenvatinib resistance through a STK24-regulated MASTL/YBX1/PAK4 signaling axis 8. MASTL also influences stemness regulators and TGF-β signaling in cancer stem cells 6. These findings establish MASTL as an emerging therapeutic target for cancer treatment.