Febrifugine, the bioactive constituent of one of the 50 fundamental herbs of 
traditional Chinese medicine, has been characterized for its therapeutic 
activity, though its molecular target has remained unknown. Febrifugine 
derivatives have been used to treat malaria, cancer, fibrosis and inflammatory 
disease. We recently demonstrated that halofuginone (HF), a widely studied 
derivative of febrifugine, inhibits the development of T(H)17-driven 
autoimmunity in a mouse model of multiple sclerosis by activating the amino acid 
response (AAR) pathway. Here we show that HF binds glutamyl-prolyl-tRNA 
synthetase (EPRS), inhibiting prolyl-tRNA synthetase activity; this inhibition 
is reversed by the addition of exogenous proline or EPRS. We further show that 
inhibition of EPRS underlies the broad bioactivities of this family of natural 
product derivatives. This work both explains the molecular mechanism of a 
promising family of therapeutics and highlights the AAR pathway as an important 
drug target for promoting inflammatory resolution.