NHEJ1 (non-homologous end joining factor 1), also known as XLF or Cernunnos, is a critical DNA repair protein that promotes the ligation of mismatched and non-cohesive DNA ends during non-homologous end joining (NHEJ). It collaborates with the Ku heterodimer and XRCC4 to facilitate double-strand break (DSB) repair and V(D)J recombination, and contributes to telomere maintenance. NHEJ1 forms bridging complexes with XRCC4 that hold broken DNA fragments in proximity while remaining mobile enough to permit access by other repair factors 12. Post-translational modifications regulate its activity; for example, lactylation of NHEJ1 at K288 enhances its binding to Ku and increases NHEJ efficiency, with implications for cancer cell chemoresistance 3. Biallelic NHEJ1 mutations cause severe combined immunodeficiency (SCID) characterized by microcephaly, growth retardation, and combined cellular and humoral immunodeficiency 4. Patients exhibit clinical variability, with reported features including recurrent infections, premature aging of hematopoietic stem cells, and telomere shortening due to downregulation of telomerase genes 5. Additionally, NHEJ1-deficient patients show markedly elevated risk for secondary myelodysplastic syndrome and acute myeloid leukemia, with 66.6% of Cernunnos-deficiency patients developing MDS/AML 6. An intronic NHEJ1 variant can affect an Indian hedgehog (Ihh) enhancer, causing microphthalmia and anophthalmia through altered expression of the neighboring Ihh gene 7. Currently, hematopoietic stem cell transplantation remains the primary therapeutic option for NHEJ1 deficiency.