Atf4, short for activating transcription factor 4, is a member of the ATF/cAMP response element-binding (CREB) family and a stress-induced transcription factor. It plays a critical role in orchestrating cellular responses to endoplasmic reticulum stress, amino acid deprivation, and oxidative challenges by regulating gene expression for cell survival [2]. It is involved in pathways like the PERK/eIF2α/ATF4/CHOP signaling pathway during endoplasmic reticulum stress [3].

In hepatocarcinogenesis, hepatocyte-specific Atf4-deficient MUP-uPA mice showed increased susceptibility to ferroptosis due to decreased expression of SLC7A11, leading to accelerated HCC development. This indicates that Atf4 suppresses hepatocarcinogenesis by blocking stress-related ferroptosis through inducing SLC7A11 [1]. In mice with Atf4 disruption specifically in intestinal epithelial cells (Atf4ΔIEC mice), they developed more severe colitis, with decreased glutamine uptake and reduced expression of antimicrobial peptides, suggesting Atf4 may be a target for treating inflammatory bowel diseases [4].

In conclusion, Atf4 is essential for maintaining cellular homeostasis under stress. Gene knockout models, such as Atf4-deficient mice in liver and intestinal epithelial cells, have revealed its crucial role in suppressing hepatocarcinogenesis and preventing intestinal inflammation. These findings contribute to understanding the mechanisms of related diseases and may provide potential therapeutic targets for liver cancer and inflammatory bowel diseases.