To investigate the biological consequences of inhibiting SKI-1/ S1P endoprotease activity on biochemical pathways of lipid homeostasis hijacked by HCV, we first employed a protein-based inhibitor strategy. We engineered and developed a novel, recombinant adenovirus expressing an effective and specific secretory pathway, SKI-1/S1P-directed serpin, Spn4A.RRLL(s). We showed that Spn4A.RRLL(s) forms a kinetically trapped heatand SDS-stable complex with SKI-1/S1P molecules characteristic of other physiological serpin-protease pairs. We then demonstrated that it blocks the SKI-1/S1P-mediated cleavage of endogenous SREBP-1 and the expression of SREBP downstream effector gene products (e.g., SREBP-2, LDLR, and PCSK9). The SREBP target gene products identified in Spn4A.RRLL(s)-treated cells are involved in lipid homeostasis and reported to participate in HCV-host interactions. SREBP-2, along with the other SREBP isoforms SREBP-1a and -1c, are activated by HCV-encoded proteins or during HCV infection [19, 31] . PCSK9 has been implicated in HCV infection through its regulation of two HCV entry factors: CD81 and LDLR [68] . Although the specific role of LDLR in HCV infection is unclear, increasing evidence indicates that LDLR promotes attachment and uptake of lipoproteinassociated HCV particles into hepatocytes [29, 69, 79, 80] .