ALPK2 (alpha kinase 2) is a cardiac-specific atypical protein kinase that plays critical roles in cardiac development and function. ALPK2 promotes cardiogenesis by negatively regulating Wnt/β-catenin signaling during cardiomyocyte differentiation, with high expression during the transition from mesoderm to cardiac progenitors in human embryonic stem cells 1. The protein prevents cardiac diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF) through phosphorylation of tropomyosin 1, which regulates myosin-actin binding and reduces cardiac stiffness 2. In non-cardiac tissues, ALPK2 functions in tumor suppression within the colon, where it promotes luminal apoptosis and DNA repair gene expression in a 3D colonic-crypt model 3. However, ALPK2 exhibits oncogenic properties in other cancers, promoting tumor progression in esophageal cancer via integrin alpha 11 4, renal cell carcinoma through Akt/mTOR signaling 5, and bladder cancer by targeting DEPDC1A 6. ALPK2 is also upregulated in metastatic high-grade serous ovarian cancer 7 and shows mutations in Epstein-Barr virus-associated lymphoproliferative disorders 8. These findings indicate ALPK2 has tissue-specific functions, acting as a cardiac protective factor while potentially promoting malignancy in various cancers.