Hepatic stellate cells (HSCs) are key mediators of liver fibrosis; however, the pathways that drive HSC migration, proliferation, and ECM production in response hepatic injury are not fully understood. In this episode, Vijay Shah and colleagues show that mice lacking the scaffold protein synectin are protected from liver fibrosis. This protection associated with down regulation of PDGFR-β and PDGFR-α via distinct synectin-regulated mechanisms, thus identifying synectin as an important mediator of liver fibrosis.