Cellular stress pathways

Cellular stress pathways are integrated signaling networks that allow cells to sense and adapt to various internal and external environmental challenges, such as proteotoxic stress, nutrient deprivation, and oxidative damage (Costa-Mattioli & Walter, 2020 [1]). These pathways, most notably the Integrated Stress Response (ISR) and the Unfolded Protein Response (UPR), converge on key regulatory nodes like the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) to modulate protein synthesis and gene expression (Hetz et al., 2020 [2]). While these responses are initially cytoprotective, chronic or excessive activation can trigger programmed cell death (apoptosis), contributing to the pathogenesis of neurodegenerative diseases like Alzheimer's and Parkinson's (Pakos-Zebrucka et al., 2016 [3]). Conversely, cancer cells often exploit these responses to survive hypoxia and chemotherapy (Galluzzi et al., 2018 [4]). Therapeutic intervention strategies focus on small molecules that can either inhibit these pathways to sensitize tumors or fine-tune them to prevent neuronal loss (Janssens et al., 2014 [5]). However, because these pathways are fundamental to cellular physiology, achieving therapeutic windows without systemic toxicity remains a significant challenge in drug development.

Other names

Cellular stress responseIntegrated stress responseProteotoxic stress responseUnfolded protein responseHeat shock responseDNA damage response

Modulation of stress-sensing kinases (e.g., PERK, GCN2, PKR, HRI), inhibition of molecular chaperones (e.g., HSP90), and regulation of transcription factors (e.g., ATF4, NRF2, HSF1) to either restore homeostasis or induce cell death.