NHEJ1 (non-homologous end joining factor 1) is a critical DNA repair protein that functions primarily in non-homologous end joining (NHEJ), the major pathway for double-strand break (DSB) repair in cells 1. NHEJ1 promotes the ligation of mismatched and non-cohesive DNA ends by working cooperatively with the Ku70/80 heterodimer and XRCC4 23. The protein functions as part of a dynamic bridging complex: it either forms alternating helical filaments with XRCC4 or engages as a single dimer that holds broken DNA fragments in close proximity while maintaining mobility to allow processing by other repair factors 45. NHEJ1 also collaborates with PAXX and DNA polymerase lambda to enable joining of non-cohesive ends, with PAXX providing functional redundancy 67. Beyond DSB repair, NHEJ1 is essential for V(D)J recombination and telomere maintenance 18. Disease-causing mutations in NHEJ1 result in severe combined immunodeficiency (SCID) characterized by microcephaly, growth retardation, and immunodeficiency 9. NHEJ1 deficiency is uniquely associated with telomere shortening through reduced telomerase gene expression and senescence 8. Patients with NHEJ1 mutations show increased susceptibility to myelodysplastic syndromes and hematological malignancies, with 66.6% developing MDS/AML 10. Emerging evidence indicates that post-translational modifications, such as lactylation at K288, enhance NHEJ1 function and chemotherapy resistance in cancer cells 11.