Naa40, also known as N-alpha-acetyltransferase 40, is a highly specific epigenetic enzyme. It catalyzes the transfer of an acetyl moiety to the alpha-amino group of serine 1 on histones H4 and H2A. This histone N-terminal acetylation is involved in regulating gene expression, chromatin function, and is associated with various biological processes such as metabolism and cancer development [1,2,3,4,5,6,7,8].

Depletion of Naa40 in CRC cell lines inhibits cell proliferation, survival, and increases their sensitivity to 5-Fluorouracil treatment. In vivo, the absence of Naa40 significantly delays the growth of human CRC xenograft tumors. Naa40 knockdown reduces the levels of symmetric dimethylation of histone H4 through transcriptional downregulation of PRMT5, leading to altered expression of key oncogenes and tumor suppressor genes [1]. In murine hepatocytes, Naa40 depletion increases intracellular acetyl-CoA levels, enhancing lipid synthesis, which is also replicated in Drosophila melanogaster larval fat body [2]. In CRC cells, Naa40 controls key one-carbon metabolic genes and metabolites, promoting resistance to antimetabolite chemotherapy [3]. In hepatocellular carcinoma, high Naa40 expression correlates with poor prognosis, and is associated with T stage, pathologic stage, etc., while having an inverse correlation with immune cell infiltration [5]. In osteosarcoma cells, Naa40 depletion reduces cell viability, migration, and invasion, and in vivo, it inhibits the proliferative and metastatic potential of these cells by epigenetically regulating AGR2 expression [6]. In colorectal cancer cells, Naa40 depletion induces p53-independent apoptosis via the mitochondrial pathway [7].

In conclusion, Naa40 plays crucial roles in multiple biological processes and diseases. Its functions in cancer, metabolism, and immune regulation have been revealed through various loss-of-function experiments including in vitro cell lines and in vivo xenograft models. These findings highlight Naa40 as a potential therapeutic target in diseases such as colorectal cancer, liver cancer, and osteosarcoma.