‘What this study adds’
-The expression of cortistatin in human and mouse livers inversely correlates with the severity of fibrosis and cirrhosis. -Treatment with cortistatin ameliorates fibrosis progression and activation of myofibroblasts in two models of hepatotoxic and cholestatic liver injury. -Deficiency in cortistatin significantly exacerbates fibrogenic responses, hepatic damage and mortality. -We identify to cortistatin as an endogenous molecular break for the activation of hepatic stellate cells and fibroblasts and for the differentiation of myofibroblasts in liver.