CENPA (centromere protein A) is a histone H3 variant that serves as the defining epigenetic mark of centromeres 1. CENPA replaces conventional H3 in centromeric nucleosomes, subtly altering nucleosome structure and DNA wrapping to create protruding DNA ends 2. This modification is essential for recruiting and assembling kinetochore proteins required for accurate chromosome 2 and mitotic progression 34. CENPA functions as an epigenetic mark that propagates centromere identity through replication and cell division 56, with recent evidence showing m6A-modified centromeric RNA stabilizes CENPA localization during S phase to preserve centromere integrity 7. Beyond canonical centromeric functions, CENPA acts as a transcriptional regulator cooperating with YY1 to drive oncogenic gene expression in hepatocellular carcinoma, with lysine 124 lactylation enhancing its transcriptional activity 8. DNA methylation patterns causally influence CENPA positioning and centromere architecture, with demethylation altering CENP-A binding and centromere function 9. PLK1-mediated phosphorylation controls CENPA deposition licensing in early G1 to replenish CENPA diluted after DNA replication 10. Loss of CENPA localization compromises centromere integrity, leading to abnormal chromosome 2 and aneuploidy 79.