PILOT PROJECT 1: PROJECT SUMMARY Hepatocellular carcinoma (HCC) is a highly fatal disease with mortality running parallel to its incidence. Lack of effective treatment for advanced HCC calls for insights into the molecular pathogenesis of HCC and development and evaluation of novel, targeted therapeutic strategies. For HCC patients, there is a statistically significant increase in incidence and mortality and a decrease in 5-year survival rates in African American (AA)/Black patients compared to non-Hispanic (white) patients. There is a gap of knowledge in our understanding of the molecular mechanism underlying the HCC racial disparity between AA/Black and white patients. Analysis of RNA-sequencing (RNA-Seq) data in the TCGA database and RNA-Seq on HCC tumor samples revealed that in both datasets the only pathway that showed statistically significant activation in AA/Black patients is the type I interferon (IFN-I) signaling pathway. This pathway is activated by Hepatitis C virus (HCV) infection, a major risk factor for HCC. Correction of the differential gene expression data based on HCV status still identified activation of IFN-I signaling pathway in AA/Black HCC patients indicating that the observed findings in AA/Black patients are independent of HCV status. HCC is a disease of chronic inflammation and IFN-Is function as pro- inflammatory and immunosuppressive cytokines, establishing the rationale for studying them. We hypothesize that persistent activation of the IFN-I signaling pathway might be a key determinant of racial disparity in AA/Black HCC patients, and even if IFN-I-inducible genes (ISGs) are induced in response to HCV infection in AA/Black patients their expression is maintained—contributing to HCC development and virulence. In this study, the role of a 4-ISG signature in regulating HCC in white and AA/Black patients will be systematically analyzed using HCC patient-derived xenograft (PDX) cell lines and the efficacy of dietary anti-inflammatory compounds in inhibiting them will be evaluated. The proposed studies will help develop a targeted therapeutic approach for AA/Black HCC patients thus having both mechanistic and therapeutic significance and innovation. Successful completion of the proposed studies will create new avenues for effective treatment of scores of AA/Black HCC patients for whom currently no effective treatment option is available.