Cell stress adaptive response (ISR) (ISR)

The cell stress adaptive response is a coordinated network of signaling pathways, most notably the Integrated Stress Response (ISR), designed to maintain cellular homeostasis under various pathological conditions such as nutrient deprivation, oxidative stress, and endoplasmic reticulum (ER) stress [1, 2]. This response is primarily regulated by four specialized kinases—PERK, GCN2, HRI, and PKR—which phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2α) in response to specific stressors [3]. Phosphorylation of eIF2α leads to a global reduction in protein synthesis to conserve energy and prevent the accumulation of misfolded proteins, while paradoxically increasing the translation of specific adaptive genes like ATF4 [3, 5]. While initially protective, chronic or excessive activation of this response can transition from a pro-survival to a pro-apoptotic state, contributing to the pathogenesis of various diseases [4]. In oncology, cancer cells often exploit this pathway to survive the harsh tumor microenvironment, making it a target for inhibition [5]. Conversely, in neurodegenerative diseases like Alzheimer's and Parkinson's, the chronic activation of the ISR contributes to synaptic loss and neuronal death, leading to therapeutic interest in ISR inhibitors or modulators to restore proteostasis [6].

Other names

Integrated stress responseCellular stress responseAdaptive stress responseProteotoxic stress response

Pharmacological modulation of the integrated stress response (ISR) typically involves targeting the phosphorylation state of eukaryotic initiation factor 2 alpha (eIF2α) or the activity of its guanine nucleotide exchange factor, eIF2B, to control global and selective protein translation [3, 5].