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Currently, no specific antiviral drugs are available to treat patients. Here, we report a natural lipid metabolite 25\u2010Hydroxycholesterol (25HC) that inhibited SFTSV entry by activating the activity of acetyl\u2010CoA\u2010cholesterol acyltransferase (ACAT), a lipid metabolism enzyme, affecting the accessible cholesterol translocation between the cytoplasm and plasma membranes (PMs). We also found that 25HC could inhibit the extracellular vesicles carrying virions into target cells, thus preventing the vesicles from mediating virus spread. In short, 25HC reduced the PMs\u2010accessible cholesterol through modulating lipid metabolism, thereby inhibiting the double infection of cells by virions and infectious EVs, and potentially reducing the efficiency of SFTSV dissemination.\n                  <\/jats:p>","DOI":"10.1096\/fj.202403337rr","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T11:14:48Z","timestamp":1755170088000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>25HC<\/scp>\n                    Depleted\n                    <scp>PMs<\/scp>\n                    \u2010Accessible Cholesterol to Restrict\n                    <scp>SFTSV<\/scp>\n                    Entry and Infectious\u2010\n                    <scp>EVs<\/scp>\n                    Mediated Infection"],"prefix":"10.1096","volume":"39","author":[{"given":"Rui","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School Nanjing University  Nanjing Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linrun","family":"Li","sequence":"additional","affiliation":[{"name":"Medical School Nanjing University  Nanjing People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siyu","family":"Li","sequence":"additional","affiliation":[{"name":"Medical School Nanjing University  Nanjing People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengxia","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School Nanjing University  Nanjing Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Cheng","sequence":"additional","affiliation":[{"name":"Medical School Nanjing University  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