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Despite their close phylogenetic relationship to influenza viruses, the mechanisms underlying their replication remain poorly understood, and the host factors mediating viral entry are unknown. Here, we performed genome-wide loss-of-function CRISPR-Cas9 screens using replication-competent recombinant vesicular stomatitis viruses expressing thogoto- and quaranjavirus glycoproteins to identify cellular determinants of viral entry. These screens identified the glycosphingolipid (GSL) biosynthesis pathway as a key regulator of viral entry, with the upstream enzyme uridine diphosphate (UDP)-glucose ceramide glucosyltransferase (UGCG) emerging as a central host entry factor. Pharmacological inhibition of UGCG impaired thogoto- and quaranjavirus entry. The importance of GSL biosynthesis for thogotovirus replication was further validated using multiple thogotovirus isolates. Together, our findings establish GSLs as critical host entry factors for non-influenza orthomyxoviruses and identify UGCG as a potential target for antiviral intervention.<\/jats:p>","DOI":"10.1099\/jgv.0.002315","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T15:16:47Z","timestamp":1786634207000},"source":"Crossref","is-referenced-by-count":0,"title":["Glycosphingolipids are essential entry factors for non-influenza orthomyxoviruses"],"prefix":"10.1099","volume":"107","author":[{"given":"Lorena","family":"Lozano-Montalb\u00e1","sequence":"first","affiliation":[{"name":"Institute for Integrative Systems Biology, CSIC-Universitat de Val\u00e8ncia, Paterna, Val\u00e8ncia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zo\u00e9","family":"Denis","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique Mol\u00e9culaire de Montpellier (IGMM), Univ Montpellier, CNRS, Montpellier, 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