The heme-regulated inhibitor eIF2α kinase: a multifaceted sensor and drug target

Heme-regulated eukaryotic translation initiation factor 2 alpha kinase (HRI) is highly expressed in red blood cell precursors and plays a critical role in their maturation by coupling globin synthesis to heme availability. HRI plays critical roles in responding to cytoplasmic and mitochondrial unfolded proteins, oxidative stress response, innate immunity, neurobiology, and the suppression of epithelial cancers. HRI activity is regulated by multiple signaling networks, which, in turn, modify cellular homeostatic responses. In this review, we summarize emerging evidence on the role of HRI in normal biology and pathobiology, the molecular underpinnings of HRI’s regulation, and discuss chemical modifiers of HRI, which may form the basis of drug development programs for the treatment of human disorders whose pathobiology can be modified by HRI.