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Chronic HDV infection is causing the most severe form of chronic viral hepatitis, leading to a rapid progression of chronic inflammation to fibrosis, cirrhosis, liver decompensation and cancer. The detailed mechanisms responsible for HDV pathogenicity and its contribution to the development of hepatocellular carcinoma (HCC) are not clearly understood. This review aims to summarize the current knowledge of HDV-induced injuries, which gradually accumulate and increase the oncogenic pressure in the liver. Here, we provide a comprehensive yet concise overview of the following topics: (1) virus sensing and innate responses, (2) molecular basis of HDV pathogenesis, and (3) pathogenesis of chronic HDV infection in patients. We summarize the compelling evidence of the direct and indirect contributions of HDV to the development of HCC, which is driven by the rapid progression to liver cirrhosis. These results led to the classification of HDV as a group 1 carcinogenic agent in 2025 and emphasize the urgent need for improved antiviral and chemopreventive treatments. In addition, it highlights the necessity of routine HDV screening in patients with chronic hepatitis B and intensified HCC surveillance in patients with chronic hepatitis D.<\/jats:p>","DOI":"10.3390\/v18030278","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T16:58:18Z","timestamp":1771952298000},"page":"278","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hepatitis D Virus Pathogenesis: A Sense of Complications"],"prefix":"10.3390","volume":"18","author":[{"given":"Yann","family":"Haennel","sequence":"first","affiliation":[{"name":"Institute of Translational Medicine and Liver Diseases (ITM), University of Strasbourg, Inserm, UMR_S1110, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8864-2168","authenticated-orcid":false,"given":"Thomas F.","family":"Baumert","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine and Liver Diseases (ITM), University of Strasbourg, Inserm, UMR_S1110, 67000 Strasbourg, France"},{"name":"Gastroenterology and Hepatology Service, Strasbourg University Hospitals, 67000 Strasbourg, France"},{"name":"Institut Hospitalo-Universitaire (IHU), 67000 Strasbourg, France"},{"name":"Institut Universitaire de France (IUF), 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3996-3907","authenticated-orcid":false,"given":"Joachim","family":"Lupberger","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine and Liver Diseases (ITM), University of Strasbourg, Inserm, UMR_S1110, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1136\/gut.18.12.997","article-title":"Immunofluorescence detection of new antigen-antibody system (delta\/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers","volume":"18","author":"Rizzetto","year":"1977","journal-title":"Gut"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8547","DOI":"10.1128\/JVI.75.18.8547-8555.2001","article-title":"Hepatitis delta virus minimal substrates competent for editing by ADAR1 and ADAR2","volume":"75","author":"Sato","year":"2001","journal-title":"J. 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