ATF5 is a basic leucine zipper transcription factor that functions as a critical regulator of cellular stress responses and developmental processes. As a transcriptional regulator, ATF5 binds to multiple DNA response elements including CRE and amino acid response elements to modulate gene expression 1. Its primary function centers on the mitochondrial unfolded protein response (UPR(mt)), where ATF5 accumulates in the nucleus during mitochondrial stress (respiratory chain dysfunction, ROS elevation, or protein folding stress) and activates protective transcriptional programs maintaining mitochondrial protein homeostasis and organelle recovery 1. During normal conditions, ATF5 localizes to mitochondria, but stress triggers cytosolic redistribution and nuclear translocation 1. In developmental contexts, ATF5 promotes neuroprogenitor cell proliferation while suppressing neuronal differentiation; trophic factors downregulate ATF5 to enable cell cycle exit and differentiation 2. ATF5 also functions in hepatocyte maturation, where it participates in generating functional induced hepatocytes with drug-metabolizing capacity 3. Additionally, ATF5 regulates mitophagy during mitochondrial stress, contributing to cellular adaptation in aging-related diseases like intervertebral disc degeneration 4. Clinically, ATF5 shows elevated expression in neural tumors including glioblastomas, neuroblastomas, and medulloblastomas, where it promotes cancer cell survival 2. Notably, cancer cells but not normal neurons require ATF5 for survival, making it a selective therapeutic target 2. Cell-penetrating peptide inhibitors of ATF5 demonstrate efficacy in suppressing brain cancer growth in preclinical and clinical trials 5.