The Integrated Stress Response in Critically Ill Patients

Introduction: Critical illness is stressful. Shock, infection, trauma and other insults alter cellular function. Cells sense and respond to these insults via interrelated pathways known collectively as the integrated stress response (ISR). The ISR is evolutionarily conserved and dramatically alters cellular transcription and translation.

Eukaryotic initiation factor 2 alpha (eiF2α) is the central regulator of the ISR and is responsible for the initiation of protein translation in the ribosomal ternary complex. Pathologic stressors are sensed by four kinases: 1) protein kinase R (PKR) senses cell injury, 2) general control non-derepressible-2 (GCN2) senses mitochondrial stress, 3) heme-regulated inhibitor kinase (HRI) senses oxidative stress, and 4) protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) links the ISR and the unfolded protein response (UPR).

Understanding ISR activation in critically ill patients has the potential to revolutionize diagnostic and therapeutic approaches in critical illness. As such, we aimed to systematically review ISR activation in critically ill patients and ISR association with outcomes.


Methods: We systematically searched MEDLINE, Embase, and Web of Science databases from inception through December 2, 2024. Eligible studies included case series, cross-sectional, case-control, cohort, or clinical trial designs evaluating the ISR in critically ill patients. Four independent reviewers screened abstracts, assessed full-text articles and extracted data. Study quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist.


Results: Of 5,659 citations, 50 studies were included (42 adult, 7 pediatric, 1 both). ISR activation was evaluated in various diseases, particularly heart disease and sepsis. The most common method for assessing ISR activation was gene expression. Key regulatory molecules and activating kinases were variably evaluated. While most studies demonstrated ISR activation, its association with outcomes was not clearly defined.


Conclusions: The ISR is activated in critical illness. Heterogeneity in disease state, methodology, and temporality led to inconsistent associations between ISR activation and outcomes. Further research is needed to elucidate the role of ISR in critical illness.