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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,3,10]]},"abstract":"<jats:p>Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis worldwide, responsible for approximately 20 million infections annually. Despite the availability of a vaccine in China, no direct-acting antivirals are approved, and host factors required for HEV replication remain poorly defined. Here, using a genome-wide CRISPR\/Cas9 knockout screen in a replicon system, we identified Eukaryotic Translation Initiation Factor 4H (EIF4H) and Y-Box Binding Protein 1 (YBX1) as essential host factors for HEV replication and pathogenesis. Knockout of either factor markedly impaired replication of HEV genotypes 1, 3, and 4, as well as HEV infection and production in hepatocellular carcinoma cells and human induced pluripotent stem cell-derived hepatocyte-like cells, while leaving SARS-CoV-2, hepatitis B virus, hepatitis C virus, and Zika virus unaffected, underscoring their HEV-specific roles. Mechanistically, EIF4H interacts with ORF1 via its methyltransferase-Y-papain-like protease region, and EIF4H deficiency alters the composition of the ORF1-associated replication complex. By contrast, YBX1 is dispensable for ORF1 translation and RNA binding but is specifically required for ORF1 proteolytic processing, a prerequisite for assembling a functional replication machinery. EIF4H knockout rats and liver-specific YBX1 knockout rats were largely resistant to rat HEV-C1 infection, showing profound reductions in viral shedding, suppressed hepatic and intestinal viral loads, and protection from liver pathology. Together, our findings establish EIF4H and YBX1 as essential host factors for HEV infection and pathogenesis and reveal potential targets for antiviral intervention.<\/jats:p>","DOI":"10.1073\/pnas.2529289123","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T18:40:32Z","timestamp":1772649632000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["EIF4H and YBX1 are essential host factors for hepatitis E virus replication and pathogenesis"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9552-0222","authenticated-orcid":false,"given":"Xiaohui","family":"Ju","sequence":"first","affiliation":[{"name":"Center for Infection Biology, School of Basic Medical Sciences, Tsinghua University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Dong","sequence":"additional","affiliation":[{"name":"Center for Infection Biology, School of Basic Medical Sciences, Tsinghua University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbial Sciences in Health, Cleveland Clinic Research, Cleveland Clinic","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuege","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Tsinghua University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael 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Q.","year":"2025","unstructured":"Z. Q. Li , YBX1 is required for assembly of viral replication complexes of chikungunya virus and replication of multiple alphaviruses. J. Virol. 99, e0201524. (2025).","journal-title":"J. Virol."},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-323665"},{"key":"e_1_3_4_61_2","unstructured":"X. Ju CRISPR\/Cas9 screen identifies host factors essential for hepatitis E virus replication. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1339010. Deposited 9 October 2025."},{"key":"e_1_3_4_62_2","unstructured":"L. Dong Proximity labeling-based proteomic analysis of the HEV ORF1-associated replication complex under EIF4H deficiency. iProX. https:\/\/www.iprox.cn\/\/page\/project.html?id=IPX0013733000. 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