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HEV infection depends on endolysosomal trafficking of virions to lysosomal compartments to initiate host cell entry. To deepen our understanding of the HEV infection cycle and support the development of novel antiviral strategies, we assessed the antiviral efficacy of compounds targeting components of the endocytic machinery.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using an established HEV cell culture model, we screened a panel of experimental and Food and Drug Administration-approved compounds targeting the endocytic pathway. Following the initial screen, the antiviral activity of apilimod was further characterised using infectivity assays, siRNA-mediated knockdown, time-of-addition experiments and mechanistic analyses of endolysosomal organisation and lysosomal protease activity. Efficacy was additionally evaluated in primary human hepatocytes and in a ratHEV infection model in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Five compounds (apilimod, raloxifen, verapamil, chloroquine and tamoxifen) inhibited HEV infection in a dose-dependent manner. The FYVE-type zinc finger containing phosphoinositide kinase (PIKfyve) inhibitor apilimod exhibited the highest antiviral potency. Requirement of PIKfyve for HEV infection was confirmed by siRNA knockdown, and time-of-addition assays demonstrated that apilimod acts during viral entry without affecting replication. Mechanistically, PIKfyve inhibition disrupted lysosomal organisation, impaired HEV trafficking to late endosomal\/lysosomal compartments and reduced lysosomal cathepsin activity. Apilimod significantly reduced HEV infectivity in primary human hepatocytes and decreased viral RNA levels in faeces and tissues in a ratHEV infection model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Overall, our data suggest that the endolysosomal protein PIKfyve plays a crucial role during the entry of HEV. Considering the reported safety profile of apilimod in previous human clinical trials, the pharmacological targeting of PIKfyve kinase activity might guide novel antiviral strategies against HEV.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/egastro-2025-100348","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T16:25:14Z","timestamp":1774974314000},"page":"e100348","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Phosphoinositide kinase PIKfyve inhibitor apilimod blocks hepatitis E virus infection"],"prefix":"10.1136","volume":"4","author":[{"given":"Julian J","family":"Ring","sequence":"first","affiliation":[{"name":"Department of Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany"},{"name":"Hepatitis E Virus Research Hub (HepE-Hub), Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Schlienkamp","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany"},{"name":"Hepatitis E Virus Research Hub (HepE-Hub), Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L","family":"Goussain Darido","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany"},{"name":"Hepatitis E Virus Research Hub (HepE-Hub), Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olinda","family":"Pinto Veiga","sequence":"additional","affiliation":[{"name":"Institute for Medical Microbiology and Virology, Carl von Ossietzky University Oldenburg, Oldenburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jil Alexandra","family":"Haase","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany"},{"name":"Hepatitis E Virus Research Hub (HepE-Hub), Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1581-8937","authenticated-orcid":false,"given":"Emely","family":"Richter","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany"},{"name":"Hepatitis E Virus Research Hub (HepE-Hub), Bochum, 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