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Pulmonary fibrosis is a scaring process related to chronic lung injury of all causes. The treatment options for pulmonary fibrosis are very limited. Rhapontin has anti-inflammatory effect and anti-proliferative activity which is widely distributed in the medicinal plants of Rheum genus in China. However, the anti-fibrotic activities of rhapontin have not been previously investigated.The effect of rhapontin on TGF-β1-mediated extracellular matrix (ECM) deposition in primary lung fibroblast (PLF) cells, on TGF-β1 secretion in LPS-stimulated human THP-1 derived macrophages in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis was investigated in vivo. Fibrotic mice were induced by intratracheal instillation of bleomycin, and then treated with rhapontin (25, 50, or 100 mg/kg/day) or prednisone (6.5 mg/kg/day, positive drug) for 2 weeks.In TGF-β1 stimulated PLFs, treatment with rhapontin resulted in a reduction of ECM with a decrease in Lox2 and p-Smad2/3. In LPS activated macrophages, treatment with rhapontin reduced TGF-β1 production. However, in vitro the attenuated ECM deposition and inflammatory response by rhapontin were closely associated with AMPK activation, and these suppression of rhapontin were significantly abolished by the AMPK inhibitor. Treatment with rhapontin for 2 weeks resulted in an amelioration of the BLM-induced pulmonary fibrosis in rats with a lower Lox2, whereas a higher AMPK expression, with reductions of the pathological score, collagen deposition, TGF-β1, α-SMA, Lox2, and HIF-1α expressions in lung tissues at fibrotic stage at 100 mg/kg.In summary, rhapontin reversed ECM, as well as Lox2 proliferation in vitro and prevented pulmonary fibrosis in vivo by modulating AMPK activation and suppressing the TGF-β/Smad pathway.Rhapontin, a stibene-type glycoside distributed widely in medicinal plants of Rheum genus (Polygonaceae), obviously ameliorates bleomycin-induced pulmonary fibrosis in mice.Rhapontin treatment effectively reversed belomycin-induced pulmonary fibrosis in mice through regulating TGF-beta/Smad pathway.The anti-inflammatory and anti-fibrotic effects of rhapontin are closely related with AMPK activation.