NAA40 (N-alpha-acetyltransferase 40) is a highly selective epigenetic enzyme that catalyzes N-terminal acetylation of histones H4 and H2A, specifically recognizing the 'Ser-Gly-Arg-Gly' sequence 12. The enzyme exists in two proteoforms: NAA40L (long form) primarily localized in the nucleus and involved in ribosome biogenesis, and NAA40S (short form) mainly cytoplasmic and acting co-translationally 3. NAA40 cooperates with the NAC complex at the ribosomal peptide tunnel exit for efficient co-translational histone acetylation 4. Beyond its canonical substrates, NAA40 also acetylates histone variants H2A.X and H2A.Z 35. The enzyme plays crucial roles in cancer progression by regulating oncogenes like PRMT5 and AGR2, contributing to chemoresistance in colorectal cancer through modulation of one-carbon metabolism and thymidylate synthase expression 678. NAA40 also influences cellular metabolism by affecting acetyl-CoA levels and lipid synthesis, with implications for insulin signaling and metabolic disorders 9. Depletion of NAA40 induces p53-independent apoptosis in cancer cells via the mitochondrial pathway, establishing its anti-apoptotic role and potential as a therapeutic target 10.