The stress responsive transcription factor ATF4: from molecular structure to disease mechanisms

• ATF4 Dual Roles: Controls stress response, amino acid synthesis, and autophagy genes, exerting dual impacts on cell survival and death. • ATF4 Regulation Under Stress: Unique structure regulated by eIF2α phosphorylation, epigenetic modifications, and post-translational modifications. • ATF4 in Diseases: Plays a key role in cancer, cardiovascular, neurodegenerative, and metabolic diseases through pathological involvement. Activating transcription factor 4 (ATF4), a member of the ATF/CREB family, regulates cell survival and death via governing the expression of genes involved in integrated stress response, endoplasmic reticulum stress, autophagy, and metabolism. ATF4′s protein level is tightly controlled by translational regulation (via eIF2α phosphorylation), epigenetic modifications, and post-translational modifications (PTMs) under stress, which are linked to cancer, cardiovascular, neurodegenerative, and metabolic diseases. This review aims to summarize recent advances in epigenetic- and PTM-mediated regulation of ATF4 stability and function, and to clarify its multifaceted roles in relevant pathological processes. Emerging evidence highlights that epigenetic modifications and PTMs are critical for fine-tuning ATF4 activity. These regulatory mechanisms not only modulate ATF4-dependent stress responses but also contribute to disease progression, providing potential therapeutic targets for ATF4-associated disorders.