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bioRxiv · 10.64898/2026.11.01.763535

XRN1-dependent RNA homeostasis regulates hepatitis D virus

Tsukuda, S.·Boutasbih, M.·Wing, P. A. C.·Fedorov, A.·Zhu, X.·Rehwinkel, J.·Balfe, P.·McKeating, J. A.
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Abstract

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis, yet the host mechanisms restricting HDV replication remain poorly understood. Although HDV infection activates the MDA5-LGP2 pathway and induces robust interferon (IFN) responses, these antiviral programs have limited impact on viral replication. Here we identify the 5-3 exoribonuclease XRN1 as a key regulator of HDV infection. Loss of XRN1 in hepatoma cells increased double-stranded RNA (dsRNA) levels and induced interferon-stimulated genes (ISGs), including MDA5 and MAVS, and limited HDV infection. XRN1 deficiency enhanced ADAR1-mediated RNA editing, revealing a dynamic interplay between endogenous dsRNA metabolism and antiviral sensing. Inhibition of type I IFN signaling restored MDA5 expression and rescued HDV replication in XRN1-deficient cells. To identify the downstream effectors responsible for this restriction, we combined transcriptomic profiling with functional siRNA screening and identified DUSP5 and SIRPA as previously unrecognized ISGs with anti-HDV activity. Together, our findings establish XRN1 as a gatekeeper of dsRNA homeostasis that controls HDV replication through innate immune activation and reveals host antiviral effectors that may provide therapeutic opportunities for chronic hepatitis D.

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Tsukuda, S., Boutasbih, M., Wing, P. A. C., Fedorov, A., Zhu, X., Rehwinkel, J., Balfe, P., McKeating, J. A.. 2026-11-02. XRN1-dependent RNA homeostasis regulates hepatitis D virus. https://doi.org/10.64898/2026.11.01.763535

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