ATF6 (activating transcription factor 6) is a key transcription factor that initiates the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress 1. Under normal conditions, ATF6 is regulated by intramembrane proteolysis and activates transcription of genes involved in the UPR, including XBP1, by binding to ER stress response elements (ERSE) 1. The protein functions as part of a three-branch UPR system alongside PERK and IRE1α pathways to restore ER proteostasis 2. ATF6 can be regulated through ubiquitin-mediated degradation, where GRINA recruits HRD1 to promote ATF6 polyubiquitination and subsequent degradation 3. However, prolonged ATF6 activation can have pathological consequences. In severe acute pancreatitis, ATF6 promotes acinar cell apoptosis through a p53/AIFM2 transcriptional pathway 4. Additionally, ATF6 contributes to colorectal cancer progression by regulating Wnt pathway signaling 5. The UPR pathway involving ATF6 is implicated in various diseases including non-alcoholic fatty liver disease 6, neurodegenerative disorders 2, and toxic proteinopathies where misfolded proteins accumulate 7. These findings highlight ATF6's dual role as both a protective cellular stress response mediator and a potential therapeutic target in various pathological conditions.