EIF2AK1 (HRI) is a metabolic stress-sensing protein kinase that phosphorylates eIF2S1 (eIF2-alpha) to activate the integrated stress response (ISR) 12. This kinase functions as a key sensor of cellular stress conditions including heme deficiency, oxidative stress, osmotic shock, and mitochondrial dysfunction 12. Upon eIF2S1 phosphorylation, global cap-dependent protein synthesis is attenuated while ISR-specific mRNAs like ATF4 are preferentially translated, enabling stress-adaptive transcriptional reprogramming 12. EIF2AK1 senses heme concentration through hemin binding; heme depletion relieves kinase inhibition and activates the ISR, crucial for coordinated hemoglobin synthesis regulation in red blood cells 12. The protein is activated during mitochondrial stress via the OMA1-DELE1 pathway: OMA1 protease cleaves DELE1, which accumulates in the cytosol and activates EIF2AK1 to trigger ATF4-mediated responses 12. Additionally, EIF2AK1 catalyzes eIF2S1 phosphorylation following S-DELE1 activation, promoting mitochondrial eIF2S1 localization and triggering PRKN-independent mitophagy 3. De novo EIF2AK1 variants cause leukoencephalopathy with developmental delay and neurologic symptoms, suggesting disrupted kinase activity impairs cellular stress adaptation 4.