Small molecule-mediated reprogramming of epithelial-mesenchymal transition thereby blocking fibrosis

Fibrotic diseases are major causes of morbidity and mortality, and the epithelial mesenchymal transition (EMT) plays a central role in the development of tissue/organ fibrosis. We discovered that eupatilin, a member of the chromone scaffold (CS) containing family of compounds found ubiquitously in the plant kingdom, completely reversed fibrogenesis in vitro and substantially ameliorated bleomycin induced lung fibrosis (BILF). Furthermore, eupatilin induced growth arrest and morphological changes in primary fibroblasts derived from a patient with idiopathic pulmonary fibrosis (IPF). To better understand fibrosis, we established a mouse hepatic stellate cell (HSC) line that robustly differentiated into myofibroblasts upon treatment with TGFb. HSC fibrogenesis was completely blocked by eupatilin, which caused dramatic morphological changes while inhibiting expression of EMT related genes. The chemical groups linked to C2, C3, C6, and C7 on the CS of eupatilin were essential for its anti fibrogenic effects. Unlike eupatilin, pirfenidone failed to block HSC fibrogenesis and did not affect the morphology of HSCs or lung fibroblasts. Although pirfenidone affected local production of TGF, as reflected by a reduction in the TGF b level in lung lysates of BILF model mice, eupatilin is likely to act via a different therapeutic mechanism. In particular, eupatilin had greater antifibrotic capacity and EMT inhibitory activity, and significantly attenuated the phosphorylation of Erk. Based on the interactome we constructed, Integrin b3 is a major player in integration of TGFb signaling and eupatilin mediated anti fibrosis. Our findings suggest that combinatorial use of eupatilin and pirfenidone may augment the therapeutic efficacy of IPF treatment.