The dual role of activating transcription factor 4: from cellular stress sentinel to cardiovascular disease intervention

As the master orchestrator of integrated stress response, activating transcription factor 4 (ATF4) operates as a central molecular switch that directs cellular fate toward survival or death by regulating genes associated with oxidative stress, endoplasmic reticulum stress, apoptosis, ferroptosis and metabolism. The functional outcome of ATF4 activation is critically dependent on the context: it usually contributes to cellular adaption and survival under mild or transient stress, yet triggers cell death when stress is severe or prolonged. Dysregulation of this dichotomous function has been implicated in a variety of diseases, such as cancer, neurodegenerative disease, metabolic disease, etc., highlighting ATF4 as a potential therapeutic target. Recently, growing evidence has further underscored the dual roles of ATF4 as the guardian or executioner in cardiovascular disorders, such as coronary heart disease, cardiomyopathy, arrhythmia, valvular heart disease, heart failure and cardiovascular aging. Here in this review, we systematically decode the context-dependent opposing roles of ATF4 in cardiovascular diseases and also highlight the underlying regulatory mechanisms, thereby providing a rationale for developing context-specific therapeutic strategies targeting ATF4 for the personalized management of cardiovascular disorders.