Citrullination has been associated with various types of diseases including cancer and autoimmune disorders, whereas the therapeutic agents modulating citrullination is not available for clinical use so far. Recently we have initiated a collaborative project of target identification of traditional Chinese medicine, and globally profiled the endogenous binding proteins of 200 natural compounds from 90 research groups using quantitative chemical-proteasome approaches. Totally we have identified more than 1000 candidate binding proteins of these natural products in 70 cell models with a diversity of tissue origins. Most of the candidates are potentially involved to the established phenotypes of the natural products that were reported by the collaborative research groups. Of note, three natural compounds were found targeting peptidyl arginine deiminases (PADIs) mediating protein citrullination. The direct binding and function modulation of these PADIs and natural products were confirmed by various methods in vitro and in vivo. Our findings provide a unique opportunity to discover lead compounds modulating endogenous PADIs for disease therapy.