Mechanism of Halofuginone Action
Halofuginone (HF) is a small molecule derived from a natural product, febrifugine, that is a potent inhibitor of fibrosis, angiogenesis, and chronic inflammation. While HF has shown promise in both animal disease models and human clinical trial, little is known about its mechanism of action. In collaboration with the lab of Dr Anjana Rao of the Immune Disease Institute, we have shown that HF selectively blocks the differentiation of Th17 cells, a pro-inflammatory T cell subtype strongly implicated in a variety of human autoimmune diseases. We have found that HF has this effect through activation of the amino acid starvation response pathway, a little-studied cytoprotective response to nutrient conditions (Sundrud et al, 2009). We have now identified the direct molecular target for HF action, an amino acyl tRNA synthetase (Keller et al, 2012, work profiled in New Scientist at http://www.newscientist.com/article/dn21462-ancient-chinese-medicine-cou...). We are currently working to understand how activation of the amino acid starvation signaling pathway by HF exerts selective effects on T cell differentiation. We are also exploring other disease models in which HF may have therapeutic effects, and studying the mechanism of HF action in non-immune cells.
Photo: the hydrangea Dichroa febrifuga, the herbal source from which febrifugine and halofuginone were originally derived.