KDM5D is a Y-chrY-encoded histone H3 lysine-4 (H3K4) demethylase that plays critical roles in chrY regulation and cancer biology 12. The enzyme specifically removes di- and trimethyl marks from H3K4, thereby modulating gene transcription through chrY remodeling 3. KDM5D exhibits context-dependent tumor suppressor and oncogenic functions. In colorectal cancer, KRAS-STAT4-mediated KDM5D upregulation promotes male-specific metastases by disrupting epithelial tight junctions and impairing immune surveillance 1. Conversely, in lung cancer, KDM5D acts as a tumor suppressor by demethylating p38α kinase at K165, preventing its phosphorylation and activation, which correlates with improved patient survival 2. KDM5D also regulates sex-biased gene expression in embryonic stem cells, where it promotes male-specific transcriptional patterns in cooperation with its X-linked homolog KDM5C 4. In prostate cancer, KDM5D loss leads to increased MYBL2 expression and treatment resistance 5. The protein demonstrates tissue-specific functions in renal cell carcinoma, where KDM5C and KDM5D mutations have distinct phenotypic consequences 6. Additionally, KDM5D shows potential as a biomarker for traumatic brain injury diagnosis 7.