ATF4 is a stress-induced transcription factor that orchestrates cellular responses to endoplasmic reticulum (ER) stress, amino acid deprivation, and oxidative challenges 1. As a member of the ATF/CREB family, ATF4 is selectively translated during ER stress via the PERK/eIF2α pathway and regulates adaptive gene expression programs 2. A critical ATF4 target is SLC7A11 (xCT), encoding a cystine/glutamate antiporter essential for glutathione synthesis, which maintains ferroptosis resistance 3. ATF4 exhibits context-dependent roles in cancer: it suppresses hepatocarcinogenesis in normal hepatocytes by preventing ferroptosis-driven inflammation and compensatory proliferation 3, yet paradoxically, cancer cells exploit ATF4 upregulation to confer therapy resistance through SLC7A11-mediated ferroptosis suppression 4. Additionally, ATF4 activates HSPA5, which protects GPX4 from degradation, limiting ferroptosis-based anticancer therapy 5. ATF4-mediated responses are regulated by post-translational modifications and epigenetic mechanisms that balance pro- and anti-survival functions 6. Clinically, ATF4 upregulation correlates with poor prognosis in hepatocellular carcinoma and other malignancies, suggesting that ATF4 inhibitors or ferroptosis inducers may overcome cancer drug resistance.