Apoptosis is critical for maintaining tissue homeostasis, and apoptosis evasion is considered as a hallmark of cancer. However, increasing evidence also suggests that proapoptotic molecules can contribute to the development of cancer, including liver cancer. The aim of this study was to further clarify the role of the proapoptotic B-cell lymphoma 2 homology domain 3 (BH3)-only protein BH3 interacting-domain death agonist (BID) for chronic liver injury (CLI) and hepatocarcinogenesis (HCG). Loss of BID significantly delayed tumor development in two mouse models of Fah-mediated and HBsTg-driven HCG, suggesting a tumor-promoting effect of BID. Liver injury as well as basal and mitogen-stimulated hepatocyte proliferation were not modulated by BID. Moreover, there was no in vivo or in vitro evidence that BID was involved in DNA damage response in hepatocytes and hepatoma cells. Our data revealed that CLI was associated with strong activation of oxidative stress (OS) response and that BID impaired full activation of p38 after OS. Conclusion: We provide evidence that the tumor-promoting function of BID in CLI is not related to enhanced proliferation or an impaired DNA damage response. In contrast, BID suppresses p38 activity and facilitates malignant transformation of hepatocytes. (HEPATOLOGY 2015;62:816-828) L iver cancer is the fifth-most common cancer in men and the ninth in women worldwide. 1 Among all cancer types, it is the second-leading cause of cancer 1 and therefore a considerable health problem. Patients with hepatocellular carcinoma (HCC), the predominant form of liver cancer, 2 are confronted with limited therapeutic options. 3 In order to develop new innovative approaches to treat and prevent tumor development in the liver, a better understanding of the underlying cellular mechanisms and molecular alterations is required.Apoptosis, the best-studied form of programmed cell death, is critical for maintaining tissue homeostasis and its deregulation is recognized as an important factor for tumorigenesis. 4,5 The decision whether a cell should live or die is largely mediated by the B-cell lymphoma 2 (BCL-2) family of anti-and proapoptotic proteins. The antiapoptotic proteins, BCL-2, BCL-2-extra large, and myeloid cell leukemia sequence 1 (MCL-1), are frequently overexpressed in HCC, 6-11 supporting the hypothesis that apoptosis resistance could contribute to Abbreviations: 4E-BP1, eIF4E binding protein 1; AKT, protein kinase B; ATM, ataxia telangiectasia mutated; BCL-2, B-cell lymphoma 2; BH3, B-cell lymphoma 2 homology domain 3; BID, BH3 interacting-domain death agonist; BrdU, bromodeoxyuridine; CLI, chronic liver injury; DEN, diethylnitrosamine; ERK, extracellular signal-regulated kinase; FAA, fumarylacetoacetate; FAH, fumarylacetoacetate hydrolase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HBsTg, HBV surface antigen transgenic; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCG, hepatocarcinogenesis; HO-1, heme oxygenase 1; IHC, immunohistochemistry; IP, immunoprecipitation; JNK, c-JUN NH2-...