NAT10, or N-Acetyltransferase-like protein 10, is an enzyme with acetyltransferase and RNA-binding activities. It is the first identified enzyme to catalyze the production of N4-acetylcytidine (ac4C) in eukaryotic RNA, which is involved in mRNA stability, translation efficiency, and various biological processes like oocyte maturation, bone remodeling, and fatty acid metabolism [1].

In multiple diseases, NAT10 shows distinct roles. In cancer, studies on cell lines and mouse models (both in vitro and in vivo) have revealed its significance. For instance, in bladder cancer, NAT10 promotes cisplatin chemoresistance by enhancing DNA damage repair through stabilizing AHNAK mRNA [2]. In cervical cancer, it reprograms glycolytic metabolism to promote malignant progression and immunosuppression [3]. In multiple myeloma, NAT10 acetylates CEP170 mRNA to enhance translation efficiency and promote cell proliferation [4]. In esophageal cancers, it promotes tumorigenesis and gefitinib resistance by modifying tRNA to enhance EGFR mRNA translation [5]. In contrast, in sepsis, neutrophil-specific over-expression of NAT10 in mice improves survival by inhibiting neutrophil pyroptosis through the ULK1-STING-NLRP3 axis, as NAT10 down-regulation in neutrophils exacerbates pyroptosis [6]. In periodontitis, the NAT10 inhibitor Remodelin reduces macrophage infiltration and bone resorption in mice, as NAT10 accelerates LPS-induced inflammation in macrophages via the NOX2-ROS-NF-κB pathway [7].

In summary, NAT10 is a crucial regulator in various biological processes and disease conditions. Model-based research, especially in mouse models, has shown its diverse functions in cancer, sepsis, and periodontitis. These findings suggest that NAT10 could be a potential target for diagnosis, therapy, and prognosis in these diseases [1].

References:

1. Xie, Lihua, Zhong, Xiaolin, Cao, Wenyu, Zu, Xuyu, Chen, Ling. 2023. Mechanisms of NAT10 as ac4C writer in diseases. In Molecular therapy. Nucleic acids, 32, 359-368. doi:10.1016/j.omtn.2023.03.023. https://pubmed.ncbi.nlm.nih.gov/37128278/

2. Xie, Ruihui, Cheng, Liang, Huang, Ming, Chen, Xu, Lin, Tianxin. . NAT10 Drives Cisplatin Chemoresistance by Enhancing ac4C-Associated DNA Repair in Bladder Cancer. In Cancer research, 83, 1666-1683. doi:10.1158/0008-5472.CAN-22-2233. https://pubmed.ncbi.nlm.nih.gov/36939377/

3. Chen, Xiaona, Hao, Yi, Liu, Yong, Zhang, Jian, Guo, Xia. 2023. NAT10/ac4C/FOXP1 Promotes Malignant Progression and Facilitates Immunosuppression by Reprogramming Glycolytic Metabolism in Cervical Cancer. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2302705. doi:10.1002/advs.202302705. https://pubmed.ncbi.nlm.nih.gov/37818745/

4. Wei, Rongfang, Cui, Xing, Min, Jie, Wang, Hongbo, Yang, Ye. 2022. NAT10 promotes cell proliferation by acetylating CEP170 mRNA to enhance translation efficiency in multiple myeloma. In Acta pharmaceutica Sinica. B, 12, 3313-3325. doi:10.1016/j.apsb.2022.01.015. https://pubmed.ncbi.nlm.nih.gov/35967285/

5. Wei, Wei, Zhang, Shuishen, Han, Hui, Choe, Junho, Lin, Shuibin. 2023. NAT10-mediated ac4C tRNA modification promotes EGFR mRNA translation and gefitinib resistance in cancer. In Cell reports, 42, 112810. doi:10.1016/j.celrep.2023.112810. https://pubmed.ncbi.nlm.nih.gov/37463108/

6. Zhang, Hao, Chen, Zhaoyuan, Zhou, Ji'an, Miao, Changhong, Chen, Wankun. 2022. NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway. In Communications biology, 5, 916. doi:10.1038/s42003-022-03868-x. https://pubmed.ncbi.nlm.nih.gov/36068299/

7. Zhang, Zhanqi, Zhang, Yiwen, Cai, Yongjie, Feng, Zhihui, Xu, Qiong. 2023. NAT10 regulates the LPS-induced inflammatory response via the NOX2-ROS-NF-κB pathway in macrophages. In Biochimica et biophysica acta. Molecular cell research, 1870, 119521. doi:10.1016/j.bbamcr.2023.119521. https://pubmed.ncbi.nlm.nih.gov/37307924/