Disease association and therapeutic routes of aminoacyl-tRNA synthetases

•Recent advances in multi-omics technologies have revealed numerous pathological implications of ARSs in various human diseases, suggesting unexpected activities beyond their canonical roles in protein synthesis.•The unique intracellular and extracellular activities of human ARSs beyond translation are opening wide opportunities to develop novel drugs for diseases that are uncurable using current targeted therapy.•Since only a portion of total ARSs is involved in epi-translational activities via non-catalytic sites, targeting these activities can exert pharmacological effects without affecting global translation. Even the catalytic sites of human ARSs can be safely targeted if the inhibitors do not severely affect global translation.•The extracellular activities mediated by the unique domains in human ARSs can be explored as a source for novel biologics. Aminoacyl-tRNA synthetases (ARSs) are enzymes that catalyze the ligation of amino acids to tRNAs for translation. Beyond their traditional role in translation, ARSs have acquired regulatory functions in various biological processes (epi-translational functions). With their dual-edged activities, aberrant expression, secretion, and mutations of ARSs are associated with human diseases, including cancer, autoimmune diseases, and neurological diseases. The increasing numbers of newly unveiled activities and disease associations of ARSs have spurred interest in novel drug development, targeting disease-related catalytic and non-catalytic activities of ARSs as well as harnessing ARSs as sources for biological therapeutics. This review speculates how the translational and epi-translational activities of ARSs can be related and describes how their activities can be linked to diseases and drug discovery. Aminoacyl-tRNA synthetases (ARSs) are enzymes that catalyze the ligation of amino acids to tRNAs for translation. Beyond their traditional role in translation, ARSs have acquired regulatory functions in various biological processes (epi-translational functions). With their dual-edged activities, aberrant expression, secretion, and mutations of ARSs are associated with human diseases, including cancer, autoimmune diseases, and neurological diseases. The increasing numbers of newly unveiled activities and disease associations of ARSs have spurred interest in novel drug development, targeting disease-related catalytic and non-catalytic activities of ARSs as well as harnessing ARSs as sources for biological therapeutic