Significance Severe human fibrotic diseases are devastating and without effective treatments. We found that c-JUN expression is increased in many human fibrotic diseases and that systemic induction of c-Jun in mice resulted in development of fibrosis of multiple organs. These results suggest that many fibrotic diseases share a common pathomechanism that converges on c-Jun induction. Thus, common treatment strategies could potentially be developed for these seemingly different fibrotic disease entities. Moreover, the in vivo c-Jun induction represents a mouse model for these devastating diseases that could be used for preclinical evaluation of candidate antifibrotic treatments. Indeed, we show that blockade of the antiphagocytotic signal CD47 and the AKT and VEGF receptor pathways reverses tissue fibrosis in mice.