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Although it is known that cytokines can inhibit HBV replication in infected hepatocytes, much is still unknown about the underlying mechanisms or mediators.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we systematically analyzed tumor necrosis factor-alpha (TNF-\u03b1) and interferon-gamma (IFN-\u03b3) induced proteins by proteomic analysis and identified interferon-inducible protein 35 (IFI35) as a novel host restriction factor for HBV replication.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Overexpression of IFI35 suppressed HBV transcription, while its reduction showed the opposite effect. Mechanistically, IFI35 regulated the stability of hepatocyte nuclear factor 4\u03b1 (HNF4\u03b1), which is essential for cccDNA transcription. IFI35 did not regulate the transcription of HNF4\u03b1 but rather promoted its degradation. We found that IFI35 recruits tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase, for K48-linked ubiquitination of HNF4\u03b1. Results were further validated using patient-derived primary human hepatocytes (PHHs) and mouse model of HBV infection. Our results revealed that cytokines, especially IFN-\u03b3, induced IFI35 in hepatocytes. IFI35 promoted the degradation of HNF4\u03b1 via the TRIM21-mediated ubiquitination, which, in turn, leads to the suppression of cccDNA transcription and viral replication.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings demonstrate that IFI35-TRIM21-HNF4\u03b1 axis may play a crucial role in TNF-\u03b1 and IFN-\u03b3 induced suppression of HBV. Consequently, these results reveal a novel antiviral action of IFI35 against HBV. These findings may hold value in the development of alternative anti-HBV drugs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01239-w","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T08:28:03Z","timestamp":1774859283000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IFI35 suppresses the transcription of hepatitis B virus cccDNA minichromosome via promoting HNF4\u03b1 proteasomal degradation"],"prefix":"10.1186","volume":"33","author":[{"given":"Nayeon","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae Jin","family":"Shin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae Won","family":"Oh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juhee","family":"Won","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ah Ram","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehrangiz","family":"Dezhbord","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeongwoo","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ki-Young","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong-Sik","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kwang Pyo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyun-Hwan","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"1239_CR1","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1016\/J.IDC.2019.08.004","volume":"33","author":"S Lanini","year":"2019","unstructured":"Lanini S, Ustianowski A, Pisapia R, Zumla A, Ippolito G. 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