HDV sensing drives USP18-mediated refractoriness to IFN-α response, sparing IFN-β/λ in hepatocytes.

Hepatitis D virus (HDV) causes the most severe form of chronic viral hepatitis, often leading to advanced liver disease and hepatocellular carcinoma. Viral cure is rarely achieved in infected patients. Interferon-alpha (IFN-α)-based therapies show suboptimal efficacy and low rates of sustained response, as reflected by their limited effect on HDV replication in vitro. Here, we show that HDV infection induces cellular resistance to IFN-α, marked by impaired STAT1 phosphorylation and reduced expression of interferon-stimulated genes (ISGs) in hepatocyte-like cells. This refractoriness depends on virus-induced innate immune activation, highlighting the role of HDV-induced ISG expression in regulating IFN signalling. We identify USP18 as a key mediator of IFN-α resistance in infected cells. Notably, ISG expression in response to type III IFN (IFN-λ) remains intact, consistent with USP18's selective inhibition of IFN-α signalling. Collectively, these findings reveal the molecular mechanism of IFN-α resistance in HDV-infected hepatocytes and provide a rationale for developing novel therapies against this major public health threat.