HCV and HBV represent the leading cause of hepatocellular carcinoma (HCC). The risk of HCC remains even after virus elimination. Thus, it is of the utmost importance to identify novel approaches to treat viral hepatitis- induced HCC. We identified a novel class of small compounds called sanglifehrin derivates (SfDer), which possess antiviral and anti-cellular activities critical for preventing viral hepatitis-induced HCC development. Recent findings highlight that our application is highly significant: i) HCC represents the fastest growing cause of cancer mortality; ii) Recent studies raised a red flag regarding unexpected higher rates of HCC recurrence following DAA treatment, indicating that viral hepatitis-associated HCC remains an unresolved and significant public health issue; iii) Patients with HCC are 8 times more likely to fail DAA treatment than patients without HCC; iv) The FDA confirmed the high risk of HBV reactivation after DAA therapy; and v) Besides sorafenib, which improves survival by only 2-3 months, >100 trials evaluating therapies for HCC failed to show survival advantages. Therefore, there is an urgent need for the identification of new combinations of drugs with distinct mechanisms of action (MoA) that concurrently inhibit HCV/HBV infections and viral hepatitis-induced HCC. We demonstrated that SfDer possess remarkable activities critical for the treatment of viral hepatitis infection and HCC: i) SfDer suppress HCV and HBV replication in vitro as well as in mice even when viral replication in implanted hepatocytes is robust; ii) SfDer are not cytotoxic even when used at high doses; iii) SfDer, but not another class of structurally distinct cyclophilin inhibitors (CypI) – cyclosporine A derivates (CsADer) – possess the unique property of stopping growth of hepatoma cells, but not that of hepatocytes; iv) SfDer inhibit in vitro and in vivo HCV and HBV replication in human hepatocytes, which are resistant to the SfDer-mediated cytostaticity, demonstrating authentic antiviral activities unrelated to their cytostatic activities; v) SfDer inhibit viral hepatitis-induced HCC; vi) SfDer inhibit HCC in a nonviral-induced HCC mouse model; and vii) SfDer modulate hepatic levels of cytokines during HCC development. Thus, SfDer represent novel attractive drugs to be part of therapies for HCV and HBV mono- and co-infections as well as viral hepatitis-induced HCC. In Aim 1, we will investigate SfDer efficacy at inhibiting viral hepatitis infection and HCC induction in mice. We will examine whether the inclusion of SfDer into DAA regimens improves their beneficial effect against viral hepatitis infection and HCC induction, whether HCV/HBV co-infection induces more severe HCC than mono- infection, and whether SfDer inhibit co-infection and co-infection-induced HCC. In Aim 2, we will investigate whether the newly identified cyclophilin A-HBx interactions, which are prevented by SfDer, are critical for HBV replication. In Aim 3, we will invest...