JMJD5: a multifunctional regulator in development, homeostasis, and cancer.

JmjC-domain-containing oxygenases are conserved epigenetic regulators whose dysfunction is closely associated with various human diseases. JMJD5, a key member of the JmjC-Domain-Only subfamily, has multiple enzymatic activities and modulates various vital physiological and pathological processes via catalytic and non-catalytic pathways. JMJD5 also displays striking tissue-specific duality in cancer: it is frequently overexpressed and acts as an oncogene in breast, prostate, and oral squamous cell carcinomas, yet is downregulated and functions as a tumor suppressor in lung, hepatocellular, and pancreatic cancers. This functional heterogeneity is closely linked to its interacting protein networks and the tumor microenvironment. Pan-cancer analyses further reveal that JMJD5 expression correlates with patient prognosis and disease progression in multiple malignancies, highlighting its potential as a prognostic biomarker. This review systematically integrates current knowledge on JMJD5 structure, enzymatic activities, physiological functions, and cancer-associated mechanisms, identifies critical research gaps, and discusses future directions for translating JMJD5 into clinical applications.