HIPK4 (homeodomain interacting protein kinase 4) is a serine/threonine protein kinase that functions as a unique member of the HIPK family 1. The protein exhibits dual-specificity kinase activity, capable of autophosphorylating on tyrosine residues for full catalytic activity, though it shows distinct subcellular localization patterns compared to other HIPKs, being excluded from the nucleus 2. HIPK4 phosphorylates several key substrates including human p53 at serine 9, leading to transcriptional repression of the survivin promoter 3. In male fertility, HIPK4 regulates spermiogenesis by phosphorylating manchette protein RIMBP3, with mutations found in patients with nonobstructive azoospermia 4. The kinase also plays opposing roles in different tissues: it inhibits human skin epithelial differentiation from iPSCs 5, while promoting cutaneous squamous cell carcinoma progression by phosphorylating TAp63 at Ser395 and reducing EFEMP1 expression 6. As a stress signal integrator, HIPK4 modulates cellular responses to DNA damage, hypoxia, and metabolic stress, making it a potential therapeutic target in proliferative diseases 7. HIPK4 has also been identified as a druggable target for nonhormonal male contraceptive development 8.