ATF3 (activating transcription factor 3) is a stress-induced transcription factor that serves as a central hub in cellular adaptive responses and metabolic homeostasis 1. ATF3 functions as both a transcriptional activator and repressor, regulating diverse cellular processes including metabolism, immunity, and cell fate determination 1. The protein operates through multiple mechanisms: it can directly bind to target gene promoters to regulate transcription, as demonstrated by its repression of SLC7A11 to promote ferroptosis 2 and its activation of PDGFRB and BCL2 in vascular smooth muscle cells 3. ATF3 also undergoes alternative splicing regulated by SRSF1, producing full-length and truncated isoforms that differentially affect angiogenesis through the KLF2-S1PR1 pathway 4. In disease contexts, ATF3 demonstrates protective functions: it prevents atherosclerosis by regulating HDL and bile acid metabolism through interactions with p53 and hepatocyte nuclear factor 4α 5, protects cardiac macrophages from apoptosis after ischemia-reperfusion injury 6, and prevents vascular smooth muscle cell senescence through an ATF3-ATG7 autophagy loop 7. However, ATF3 can also promote cancer-associated metabolic reprogramming, as shown in glioblastoma where it regulates P4HA1/succinate signaling 8. These diverse functions position ATF3 as a master regulator with significant therapeutic potential across cardiovascular, metabolic, and oncological diseases.