DYRK2 (dual specificity tyrosine phosphorylation regulated kinase 2) is a serine/threonine kinase that plays complex, context-dependent roles in cellular homeostasis and cancer biology 1. The kinase functions as a critical regulator of cell cycle progression, DNA damage response, and apoptosis through phosphorylation of key substrates including p53 at Ser46, promoting apoptosis following DNA damage 23. DYRK2 exhibits dual regulatory mechanisms in cancer, functioning either as a tumor suppressor by facilitating degradation of oncogenic proteins like c-Myc and SNAIL, or paradoxically as an oncogene by enhancing proteasome function and promoting therapy resistance in specific cancer contexts 4. In Hedgehog signaling, DYRK2 acts as a positive regulator by phosphorylating GLI2 and GLI3 transcription factors, promoting their dissociation from the suppressor SUFU and nuclear translocation 5. The kinase also participates in a novel feedback loop with USP28, where DYRK2 promotes USP28 degradation while USP28 stabilizes DYRK2, collectively regulating oncogenic protein homeostasis 3. Clinically, DYRK2 represents a promising therapeutic target, with selective inhibitors showing efficacy in prostate cancer models, though its dual tumor suppressor/oncogenic roles necessitate careful cancer subtype stratification for therapeutic applications 64.