Atf3, short for activating transcription factor 3, is a stress-induced transcription factor belonging to the ATF/cAMP-responsive element-binding (CREB) protein family. It acts as a key regulator in multiple biological processes, functioning as either a transcriptional activator or repressor by forming dimers with other ATF/CREB members. It is involved in pathways related to metabolism, immunity, and cellular stress responses, and is of great biological importance in maintaining metabolic homeostasis and normal physiological cell function [4].

In abdominal aortic aneurysm (AAA) development, ATF3 shows a spatiotemporal expression pattern. Deficiency of ATF3 in vascular smooth muscle cells (VSMCs) promoted AAA formation in Ang II-induced AAA mice. PDGFRB was identified as its target, mediating VSMC proliferation at the early stage of AAA, and ATF3 suppressed mitochondria-dependent apoptosis at the advanced stage by upregulating BCL2. Also, NFKB1 inhibitor promotes AAA development by blocking the recruitment of NFKB1 and ATF3-enhancer to the ATF3-promoter region [1]. In atherosclerosis, ATF3 has distinct roles in different cell types. In endothelial cells, its overexpression aggravates oxidative stress and inflammation, while in macrophages and liver cells, it can act as a negative regulator of inflammation and promote cholesterol metabolism [2]. In metabolic dysfunction-associated steatohepatitis (MASH), macrophage-specific Atf3 overexpression protects against MASH development in Western diet-fed mice, while Atf3 ablation has the opposite effect. Atf3 regulates the glucose-fatty acid cycle in macrophages, affecting hepatocyte steatosis and hepatic stellate cell fibrogenesis [3]. In the context of cancer, in thyroid cancer, promoter DNA hypermethylation of ATF3 decreased its expression, promoting cancer progression by regulating prognosis-related genes in the MAPK and PI3K/AKT pathways [5].

In conclusion, Atf3 is a crucial transcription factor involved in diverse biological processes. Through gene knockout (KO) or conditional knockout (CKO) mouse models, its roles in diseases such as AAA, atherosclerosis, MASH, and thyroid cancer have been revealed. These models have provided insights into how Atf3 regulates metabolism, inflammation, apoptosis, and cell proliferation, which may contribute to the development of targeted therapies for these diseases.

References:

1. Wen, Ying, Liu, Yingying, Li, Qiang, Zhang, Yuan, Tang, Wai Ho. 2024. Spatiotemporal ATF3 Expression Determines VSMC Fate in Abdominal Aortic Aneurysm. In Circulation research, 134, 1495-1511. doi:10.1161/CIRCRESAHA.124.324323. https://pubmed.ncbi.nlm.nih.gov/38686580/

2. Wang, Bingyu, Yang, Xi, Sun, Xinyi, Lian, Jiangfang, Zhou, Jianqing. 2022. ATF3 in atherosclerosis: a controversial transcription factor. In Journal of molecular medicine (Berlin, Germany), 100, 1557-1568. doi:10.1007/s00109-022-02263-7. https://pubmed.ncbi.nlm.nih.gov/36207452/

3. Hu, Shuwei, Li, Rui, Gong, Dongxu, Wu, Huijuan, Xu, Yanyong. 2024. Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis. In Science advances, 10, eado3141. doi:10.1126/sciadv.ado3141. https://pubmed.ncbi.nlm.nih.gov/39047111/

4. Ku, Hui-Chen, Cheng, Ching-Feng. 2020. Master Regulator Activating Transcription Factor 3 (ATF3) in Metabolic Homeostasis and Cancer. In Frontiers in endocrinology, 11, 556. doi:10.3389/fendo.2020.00556. https://pubmed.ncbi.nlm.nih.gov/32922364/

5. Xiao, Xi, Chen, Mengke, Sang, Ye, Liu, Rengyun, Xiao, Haipeng. 2023. Methylation-Mediated Silencing of ATF3 Promotes Thyroid Cancer Progression by Regulating Prognostic Genes in the MAPK and PI3K/AKT Pathways. In Thyroid : official journal of the American Thyroid Association, 33, 1441-1454. doi:10.1089/thy.2023.0157. https://pubmed.ncbi.nlm.nih.gov/37742107/