In this study, we demonstrate that (i) metformin ameliorates TGF-β1-induced EMT of peritoneal mesothelial cells and animal model of PD; (ii) the beneficial effect of metformin on EMT and peritoneal fibrosis is attributed to an inhibition of ROS generation, Smad2/3, ERK and p38 MAPKinase activation; (iii) the effect of metformin is independent of AMPK activation at early time points, however can be mediated by AMPK at later time points; (iv) metformin also protects the peritoneum from EMT and fibrosis by reinforcing local anti-oxidant activity. The gene discussed is TGFB1; the disease is Peritoneal Fibrosis.