Development of specific antivirals is an urgent unmet need for SARS-coronavirus 2 (SARS-CoV-2) infections. This study focuses on host proteases that proteolytically activate the SARS-CoV-2 spike protein, critical for its fusion after binding to angiotensin-converting enzyme 2 (ACE2), as antiviral targets. We first validated cleavage at a putative furin substrate motif at SARS-CoV-2 spike by expressing it in VeroE6 cells and found prominent syncytium formation. Both cleavage and syncytium were abolished by treatment with furin inhibitors decanoyl-RVKR-chloromethylketone (CMK) and naphthofluorescein but not by transmembrane protease serine 2 (TMPRSS2) inhibitor camostat. CMK and naphthofluorescein showed antiviral effects in SARS-CoV-2-infected cells by decreasing viral production and cytopathic effects. Further analysis revealed that, similar to camostat, CMK blocks virus entry, but it further suppresses the cleavage of spike and syncytium. Naphthofluorescein instead acts primarily by suppressing viral RNA transcription. Therefore, furin inhibitors may become promising antivirals for prevention and treatment of SARS-CoV-2 infections.

Most hepatocellular carcinomas (HCCs) develop in patients with chronic hepatitis, which creates a microenvironment for the growth of hepatic progenitor cells (HPCs) at the periportal area and subsequent development of HCCs. We investigated the signal from the inflammatory liver for this pathogenic process in the hepatic conditional β-catenin knockout mouse model. Senescent β-catenin–depleted hepatocytes in aged mice create an inflammatory microenvironment that stimulates periportal HPC expansion but arrests differentiation, which predisposes mice to the development of liver tumors. The release of complement C1q from macrophages in the inflammatory niche was identified as the unorthodox signal that activated the β-catenin pathway in periportal HPCs and was responsible for their expansion and de-differentiation. C1q inhibitors blocked the β-catenin pathway in both the expanding HPCs and the liver tumors but spared its orthodox pathway in pericentral normal hepatocytes. This mechanism has been validated in human liver specimens from patients with chronic hepatitis. Taken together, these results demonstrate that C1q- mediated activation of β-catenin pathway in periportal HPCs is a previously unrecognized mechanism for replenishing hepatocytes in the inflammatory liver and, if unchecked, for promoting hepatocarcinogenesis. C1q may become a new target for blocking carcinogenesis in patients with chronic hepatitis.