KDM8 (lysine demethylase 8) is a bifunctional histone-modifying enzyme that plays crucial roles in cell cycle regulation, metabolism, and cancer progression. As a histone H3K36me2 demethylase, KDM8 functions as a transcriptional activator by preventing HDAC recruitment and directly regulates cyclin A1 expression in the coding region, which is essential for cell cycle progression 1. The enzyme also acts as an endopeptidase that cleaves histone N-terminal tails at methylated residues, generating 'tailless nucleosomes' that may facilitate transcription elongation. In cancer contexts, KDM8 demonstrates oncogenic properties through multiple mechanisms. In prostate cancer, it serves as a dual coactivator of androgen receptor (AR) and PKM2, promoting castration resistance by elevating androgen response genes and facilitating PKM2 nuclear translocation for metabolic reprogramming 2. KDM8 also partners with PKM2 to enhance HIF1α-mediated transactivation, particularly in breast cancer cells with PKM2 exon-10 mutations 3. Beyond cancer, KDM8 plays protective roles in cardiac metabolism by repressing TBX15 to maintain mitochondrial gene networks, preventing dilated cardiomyopathy 4. Additionally, KDM8 regulates autophagy through BECN1 dimethylation, with ADSL-produced fumarate reducing KDM8 activity to promote autophagy in liver tumors 5. Clinical significance is evident as KDM8 is overexpressed in multiple cancer types and downregulated in hepatocellular carcinoma due to CpG hypermethylation 6.