salubrinal

Salubrinal is a cell-permeable, selective inhibitor of the phosphatase complexes that dephosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α)[1][10]. By inhibiting eIF2α dephosphorylation, salubrinal prolongs the phosphorylation state of eIF2α, which is a key regulator of the integrated stress response and the unfolded protein response. This leads to a temporary halt in global protein synthesis while selectively promoting the translation of stress-responsive genes, such as ATF4 and CHOP, which orchestrate cellular responses to endoplasmic reticulum (ER) stress and other stresses[2][3]. Salubrinal is widely used as a research tool to study cellular stress pathways and has demonstrated protective effects against ER stress-induced apoptosis in preclinical models[1][7]. There is emerging preclinical evidence suggesting potential therapeutic applications in osteoporosis, cancer (including inflammatory breast cancer), and possibly ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) and long-COVID, but as of now, it is not approved for clinical use and remains experimental[2][3][4]. Salubrinal has also been shown to interact with the anti-apoptotic protein Bcl-2, inhibiting the binding of antagonists and protecting cells from apoptotic and autophagic effects induced by loss of Bcl-2 function[7]. Importantly, while phosphorylation of eIF2α is generally cytoprotective in the context of stress, sustained activation by salubrinal can drive cells toward apoptosis under prolonged or severe stress conditions, highlighting the context-dependent nature of its effects[2][8].