Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease of unknown cause. Under the pathogenic environment, myofibroblasts (MyoFs) mainly differentiated from fibroblasts play a key role in lung fibrogenesis. Established MyoF has been considered as an irreversible phenotype, but recently shown to dedifferentiate to fibroblast. This feature is desirable in development of pharmacologic strategy against IPF because most patients with IPF appear to accumulate pathogenic MyoFs in their lungs at the time of clinical presentation. Therefore, we have established several strains of primary cultured MyoFs from the fibrotic lungs of patients. Using our MyoF assay system, the drug library for compounds that inhibit epigenetics-related signals was screened by monitoring downregulation in expression of collagen and MyoF markers, α-SMA and ED-A fibronectin. Through this assay, we found in vitro that a certain histone methyltransferase inhibitor potently dedifferentiated MyoFs. In addition, intratracheal administration with the compound at the early fibrotic stage of bleomycin-injured lung successfully ameliorated lung fibrosis in mice. We will discuss the mechanism by which the compound affects pathogenic myofibroblast under lung fibrogenesis.