The dual role of ATF4 in neurons: from stress adaptation to therapeutic intervention

Activating transcription factor 4 (ATF4) functions as the central transcriptional arbiter of the integrated stress response (ISR) in neurons. Its translation is gated by diverse upstream kinases via the eIF2α pathway, while its functional output is critically shaped by context-dependent interactions with specific protein partners (e.g., C/EBPβ or CHOP). We conceptualize ATF4 as a spatiotemporal rheostat whose regulatory mandate is stage-specific: it acts as a physiological switch during neocortical development and maintains synaptic and mitochondrial integrity in the adult brain. However, this precise regulation fails in neurological disorders, including Alzheimer's disease, Parkinson's disease, cerebral ischemia, and epilepsy. Chronic, maladaptive ATF4 signaling-often driven by pathological heterodimerization-catalyzes neuroinflammation, ferroptosis, and circuit failure. Crucially, contemporary challenges in clinical translation highlight a "therapeutic paradox," where broad or untimely pathway inhibition may inadvertently dismantle essential neuroprotective shields. We therefore advocate for a paradigm shift toward "kinetic recalibration"-the development of precision interventions designed to restore the proteostatic and information-processing homeostasis of the stressed nervous system.