SRP310411 PRJNA714069 Cortistatin regulates liver fibrosis and hepatic stellate cell activation Liver fibrosis, which occurs as result of chronic liver disease, is associated with severe morbidity and mortality. It is consequence of the replacement of functional parenchyma by fibrous scar due to an excessive production/accumulation of extracellular matrix by myofibroblasts. In normal liver, myofibroblast are absent but in response to injury they transdifferentiate from hepatic stellate cells (HSCs), and because of that it is urgent to identify endogenous factors that regulate these pathological processes. Evidences indicate that the anti-inflammatory neuropeptide cortistatin is a gene involved in the regulation of liver fibrosis. Fibroblast and HSCs express cortistatin and its gene expression decreased with profibrogenic stimuli in vitro and in vivo. Moreover, in two preclinical mouse models of toxic and cholestasis-induced liver fibrosis, we found that total- or partial-deletion of cortistatin gene predisposes to develop exacerbated fibrogenic responses and more severe liver failure and mortality. Transcriptomic analysis of cortistatin-deficient HSCs by RNAseq showed a genetic program consistent with an activated myofibroblastic phenotype. Interestingly, lack of cortistatin also caused that HSCs differentially expressed a plethora of genes critically involved in muscle cell differentiation and function, genes that were absent in wild-type HSCs. These results have important pathological implications, since acquisition of muscle-like characteristics by myofibroblasts is a final step in their differentiation pathway in fibrotic liver and is a hallmark of irreversible hepatic fibrosis and organ failure. Importantly, treatment with cortistatin reversed the exacerbated fibrotic and contractile phenotype observed in cortistatin-deficient animals and HSCs. Our findings demonstrate that cortistatin gene acts as an endogenous break for fibrotic responses in liver and that limits the pathogenic activation and transdifferentiation of myofibroblasts from HSCs. They suggest the potential of considering low cortistatin levels as biomarker of susceptibility and severity in hepatic fibrosis-associated diseases, and that cortistatin-based interventions emerge as attractive therapeutic strategies to treat them.