The Janus framework of the integrated stress response: from homeostasis to maladaptation

Every cell must adapt to environmental changes. When nutrients decrease, oxygen levels fall, or protein synthesis outpaces resources, cells activate stress pathways to restore balance. Among these, the integrated stress response (ISR) stands out for its capability to integrate diverse stress signals into a unified translational output. By temporarily slowing global protein synthesis while maintaining the selective translation of stress-adaptive factors, the ISR saves energy, redirects metabolism, and promotes either recovery or, if challenges surpass repair capacity, cell death. In many chronic diseases-including cancer, metabolic, inflammatory, and fibrotic disorders-ISR activity persists. Is this persistence merely a prolonged defensive phase, or does it represent a rewired, self-sustaining state with its own control mechanisms actively reshaping cell fate and disease? We argue that chronic ISR cannot be defined by time alone, challenging the monolithic view. It signifies a qualitative shift in regulation-from rhythmic homeostasis to entrenched maladaptation. Understanding this Janus framework is essential for elucidating the origins of pathology and for guiding future fundamental and translational research.