“ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis”. Here, we identify soluble ephrin-B2 as a new profibrotic mediator in lung and skin fibrosis. Mechanistically, TGF-β induces ADAM10 expression, which results in greater ephrin-B2 shedding. This shedding promotes organ fibrosis. Our results uncover a new molecular mechanism of tissue fibrogenesis and identify sEphrin-B2, its receptors EphB3 and EphB4 and ADAM10 as potential therapeutic targets in the treatment of fibrotic diseases.