General control nonderepresible 2 (GCN2) is a highly conserved cytosolic kinase that modulates a complex response for coping with the stress owing to lack of amino acids. GCN2 has been recently shown to be involved in the regulation of metabolic balance and lipid degradation rate in the liver. We hypothesized that GCN2 could have a role in in hepatic fibrogenesis and in the response to acute or chronic liver injury. Activation of GCN2 in primary or immortalized human hepatic stellate cells by incubation with medium lacking the essential amino acid histidine correlated with decreased levels of collagen type I protein and mRNA, suggesting an antifibrogenic effect of GCN2. In vivo studies with Gcn2 knock-out mice (Gcn2(-/-)) showed increased susceptibility to both acute or chronic liver damage induced by CCl(4), as shown by higher alanine aminotransferase and aspartate aminotransferase activities, increased necrosis and higher inflammatory infiltrates compared with wild-type mice (WT). Chronic CCl(4) treatment increased deposition of interstitial collagen type I more in Gcn2(-/-) mice than in WT mice. Col1a1 and col1a2 mRNA levels also increased in CCl(4)-treated Gcn2(-/-) mice compared with WT mice. These results suggest that GCN2 is a key regulator of the fibrogenic response to liver injury.Laboratory Investigation advance online publication, 14 January 2013; doi:10.1038/labinvest.2012.173.