CLK2 (CDC-like kinase 2) is a dual-specificity kinase that phosphorylates both serine/threonine and tyrosine residues, playing critical roles in RNA splicing regulation and cellular stress responses. CLK2 phosphorylates serine/arginine-rich (SR) splicing factors, modulating alternative splicing patterns and intron retention 1. The kinase undergoes liquid-liquid phase separation within nuclear speckles during stress conditions, forming condensates that reorganize nuclear architecture and promote intron retention by sequestering splicing factors 2. CLK2 also regulates the NF-κB inflammatory pathway through IκBα-independent mechanisms, phosphorylating RelA/p65 at Ser180 to promote its degradation and nuclear export, thereby providing rapid termination of NF-κB activation 3. In cancer contexts, CLK2 functions as a ferroptosis suppressor by stabilizing KEAP1 to inhibit NRF2 activity and downregulating p53, which disrupts the balance between pro-ferroptotic HMOX1 and anti-ferroptotic SLC7A11 4. CLK2 promotes tumor progression in pancreatic cancer through enhanced translation efficiency via PABPC1 deubiquitination 5. Therapeutically, CLK2 represents a promising target for osteoarthritis treatment through Wnt pathway inhibition 67, while genetic variants in CLK2 are associated with early-onset cerebellar atrophy 8.