For roughly two thousand years, Chinese herbalists have treated Malaria¹ using a root extract, commonly known as Chang Shan, from a type of hydrangea（绣球花） that grows in Tibet and Nepal. More recent studies suggest that halofuginone（卤夫酮） , a compound derived² from this extract's bioactive ingredient, could be used to treat many autoimmune disorders³ as well. Now, researchers from the Harvard School of Dental Medicine have discovered the molecular⁴ secrets behind this herbal extract's power. It turns out that halofuginone (HF) triggers a stress-response pathway that blocks the development of a harmful class of immune cells, called Th17 cells, which have been implicated⁵ in many autoimmune disorders.

"HF prevents the autoimmune response without dampening immunity⁶ altogether," said Malcolm Whitman, a professor of developmental biology at Harvard School of Dental Medicine and senior author on the new study. "This compound could inspire novel therapeutic⁷ approaches to a variety of autoimmune disorders."

"This study is an exciting example of how solving the molecular mechanism⁸ of traditional herbal medicine can lead both to new insights into physiological⁹ regulation and to novel approaches to the treatment of disease," said Tracy Keller, an instructor¹¹ in Whitman's lab and the first author on the paper.

This study, which involved an interdisciplinary（各学科间的） team of researchers at Massachusetts General Hospital and elsewhere, will be published online February 12 in Nature Chemical Biology.

Prior research had shown that HF reduced scarring in tissue, scleroderma（硬皮病） (a tightening¹² of the skin), multiple sclerosis, scar formation and even cancer progression. "We thought HF must work on a signaling pathway that had many downstream effects," said Keller.

In 2009, Keller and colleagues reported that HF protects against harmful Th17 immune cells without affecting other beneficial immune cells. Recognized only since 2006, Th17 cells are "bad actors," implicated in many autoimmune diseases such as inflammatory bowel¹³ disease, rheumatoid arthritis¹⁴（风湿性关节炎） , multiple sclerosis and psoriasis（牛皮癣） . The researchers found that minute doses of HF reduced multiple sclerosis in a mouse model. As such, it was one of a new arsenal¹⁵ of drugs that selectively inhibits¹⁶ autoimmune pathology without suppressing the immune system globally. Further analysis showed that HF was somehow turning on genes¹⁷ involved in a newly discovered pathway called the amino acid response pathway, or AAR.

Scientists have only recently appreciated the role of the nutrient¹⁸ sensing-AAR pathway in immune regulation and metabolic¹⁹ signaling. There is also evidence that it extends lifespan and delays age-related inflammatory diseases in animal studies on caloric restriction²⁰. A conservationist of sorts, AAR lets cells know when they need to preserve resources. For example, when a cell senses a limited supply of amino acids for building proteins, AAR will block signals that promote inflammation because inflamed²¹ tissues require lots of protein.

"Think about how during a power outage we conserve²² what little juice we have left on our devices, foregoing chats in favor of emergency calls," said Whitman. "Cells use similar logic¹⁰."