Pulmonary fibrosis is characterized by lung fibroblast activation and ECM deposition and has a poor prognosis.Heat shock protein 90 (Hsp90) participates in organ fibrosis and extracellular Hsp90α (eHsp90α) promotes fibroblast activation and migration. This study aimed to investigate whether a selective anti-Hsp90α monoclonal antibody, 1G6-D7, could attenuate lung fibrosis and whether 1G6-D7 presents protective effect by inactivating profibrotic pathway.Our results showed that eHsp90α was increased in mice with BLM-induced pulmonary fibrosis and that 1G6-D7 attenuated inflammation and collagen deposition in the lung. TGF-β1 induced eHsp90α secretion, concomitantly promoting HFL-1 activation and ECM synthesis.1G6-D7-mediated inhibition of eHsp90α significantly blocked these effects,meanwhile inhibiting downstream profibrotic pathways such as ERK, AKT, and P38.Human recombinant (hr)Hsp90α mimicked the effects of TGF-β1, by activating profibrotic pathways and by upregulating LRP-1.Moreover,ERK inhibition effectively blocked the effect of (hr)Hsp90α.In conclusion, 1G6-D7 significantly protects against BLM-induced pulmonary fibrosis by ameliorating fibroblast activation and ECM production,which may be through blocking ERK signaling. Our results suggest a safer molecular therapy, 1G6-D7, in pulmonary fibrosis.