PLK5 (polo-like kinase 5) is an inactive serine/threonine-protein kinase that functions primarily in neuronal differentiation and DNA damage response rather than canonical cell cycle progression 1. The protein localizes to the nucleolus and responds to DNA damage, with ectopic expression inducing G1 cell cycle arrest and apoptosis 2. Unlike active PLK family members (PLK1-4), PLK5 exhibits apparent loss of catalytic activity despite retaining a functional polo-box domain involved in substrate recognition 1. Clinically, PLK5 functions as a tumor suppressor. In breast cancer, high PLK5 expression correlates with improved recurrence-free survival, contrasting with oncogenic PLK1 and PLK4 3. Similarly, decreased PLK5 protein and mRNA levels in non-small cell lung cancer associate with increased pathological grade, lymph node metastasis, and shortened disease-free survival 4. In inflammatory breast cancer, reduced PLK5 mRNA expression correlates with lower activated mast cell abundance and poorer prognosis 5. PLK5 has also been identified as a novel genetic risk locus for Hirschsprung's disease, a congenital enteric neuropathy 6. These observations suggest PLK5 functions as a kinase-independent tumor suppressor through polo-box domain-mediated mechanisms, making it a potential biomarker for cancer prognosis rather than a therapeutic target 7.