{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "University of Oxford"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "name": "S. Tsukuda"
    },
    {
      "name": "M. Boutasbih"
    },
    {
      "name": "P. A. C. Wing"
    },
    {
      "name": "A. Fedorov"
    },
    {
      "name": "X. Zhu"
    },
    {
      "name": "J. Rehwinkel"
    },
    {
      "name": "P. Balfe"
    },
    {
      "affs": [
        0
      ],
      "name": "J. A. McKeating"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/be9qfyqepqfzf.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.01.763535",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.11.01.763535v1.full",
  "id": "be9qfyqepqfzf",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.11.01.763535v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "molecular biology"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.11.01.763535v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/be9qfyqepqfzf.ris",
  "sources": [
    {
      "first_seen": "2026-11-03T00:20:41Z",
      "native_id": "10.64898/2026.11.01.763535",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.11.01.763535v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:molecular biology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "XRN1-dependent RNA homeostasis regulates hepatitis D virus",
  "title_text": "XRN1-dependent RNA homeostasis regulates hepatitis D virus",
  "type": "preprint",
  "updated_at": "2026-11-04T00:21:11Z",
  "url": "https://research.draconitic.com/paper/be9qfyqepqfzf",
  "venue": "bioRxiv",
  "versions": []
}