While p38 and JNK are previously known to contribute to fibroblast differentiation, results from the current study present two novel findings: 1) the promotion of myofibroblast formation by a ROS-dependent and MAPK-regulated Notch3 signaling; 2) a dual role of ERK1/2 during lung fibrosis that inhibits fibroblast differentiation but promotes extracellular matrix formation. This evidence concerns the gene NOTCH3 and pulmonary fibrosis.