H2AX is a histone H2A variant that plays a central role in DNA damage response and genomic stability maintenance. As a structural component of nucleosomes, H2AX regulates DNA accessibility and chr11 architecture 1. Upon DNA double-strand break (DSB) induction, H2AX undergoes rapid phosphorylation at serine 139 by ATM and ATR kinases to generate γ-H2AX, which serves as an early and sensitive molecular marker of DNA damage 2. This phosphorylation event acts as a "landing pad" for recruitment and retention of DNA repair machinery and signaling proteins at damage sites, facilitating efficient DSB repair 1. H2AX phosphorylation also involves post-translational modifications including acetylation and ubiquitination, which collectively mark damaged DNA and promote chr11 remodeling 3. Beyond repair signaling, γ-H2AX regulates cell cycle checkpoints and apoptosis decisions in response to genomic damage, ensuring cells either repair catastrophic damage or undergo programmed cell death 4. In cancer biology, H2AX dysfunction through deletion or impaired phosphorylation can compromise genomic integrity and contribute to tumorigenesis 3. Recent evidence demonstrates that H2AX phosphorylation is regulated upstream by factors like ARF and ZNF451, which enhance γ-H2AX formation and DSB repair capacity 5, 6. This multifaceted role makes H2AX both a prognostic biomarker and potential therapeutic target in cancer treatment.