Atf3, an activating transcription factor 3, is a member of the ATF/CREB (cAMP response element-binding protein) family. It acts as a master regulator of the adaptive response, functioning as either a transcription suppressor or activator by forming dimers with other ATF/CREB members. It is involved in multiple pathways, including those related to metabolism, immunity, and cell survival, and is thus of great biological importance. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions [2,4,5].

In abdominal aortic aneurysm (AAA), ATF3 deficiency in vascular smooth muscle cells promoted AAA formation in Ang II-induced AAA mice. PDGFRB was identified as its target, mediating cell proliferation at the early stage, and ATF3 suppressed mitochondria-dependent apoptosis at the advanced stage by upregulating BCL2. NFKB1 inhibitor led to AAA development by inhibiting ATF3 expression [1]. In atherosclerosis, its role is controversial. In endothelial cells, 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), Atf3 overexpression in macrophages protects against MASH development in Western diet-fed mice, while ablation has the opposite effect, as it regulates the glucose-fatty acid cycle [3].

In conclusion, Atf3 is a key regulator in multiple biological processes and diseases. Through KO/CKO mouse models, its role in diseases like AAA, atherosclerosis, and MASH has been revealed. It is involved in cell fate determination, inflammation regulation, and metabolic reprogramming, highlighting its potential as a therapeutic and prognostic marker in these disease areas [1,2,3].