The Yin–Yang of Stress and Senescence: Integrated Stress Response and SASP Crosstalk in Stem Cell Fate, Regeneration, and Disease

Stem cell fate decisions are increasingly understood through the dynamic interplay of two fundamental stress-adaptive programs: the integrated stress response (ISR) and the senescence-associated secretory phenotype (SASP). These pathways act as a Yin-Yang system, balancing beneficial and detrimental outcomes across development, tissue homeostasis, and disease. On the yin (protective) side, transient ISR activation and acute SASP signaling foster adaptation, embryonic patterning, wound healing, and regeneration. On the yang (maladaptive) side, chronic ISR signaling and unresolved SASP output drive stem cell exhaustion, fibrosis, inflammation, and tumorigenesis. This duality highlights their roles as both guardians and disruptors of stem cell integrity. Mechanistically, ISR regulates translational control via eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation and activating transcription factor 4 (ATF4)-dependent transcription, while SASP reprograms the extracellular milieu through cytokines, growth factors, and proteases. Their crosstalk creates feedback loops that shape tissue niches and long-term stem cell potential. Framing ISR-SASP interactions through a Yin-Yang lens underscores the balance between resilience and decline, to offer new insights into regenerative medicine, anti-aging interventions, and cancer therapeutics.