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Here we identify the host soluble inositol phosphate pathway as a previously unrecognized dependency for coronavirus infection. Genetic or pharmacologic inhibition of several kinases in this pathway markedly suppresses replication of both alpha- and betacoronaviruses, while increasing pathway activity promotes viral replication. We developed UNC7844, a potent multi-target inhibitor of these kinases, which reduces coronavirus replication by more than four orders of magnitude in cultured cells and suppresses coronavirus infection in mice. Mechanistically, UNC7844 suppresses inositol (pyro)phosphates production, disrupts phosphoinositide homeostasis, and impairs late endosomal dynamics, blocking early post-entry steps required for viral genome release and replication. Together, our findings establish the soluble inositol (pyro)phosphate pathway as an important regulator of coronavirus infection and highlight its inhibition as a promising host-directed antiviral strategy.<\/jats:p>","DOI":"10.64898\/2026.09.12.751050","type":"posted-content","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T03:20:15Z","timestamp":1789528815000},"source":"Crossref","is-referenced-by-count":0,"title":["Host soluble inositol phosphate signaling promotes coronavirus replication"],"prefix":"10.64898","author":[{"given":"Igor","family":"Shats","sequence":"first","affiliation":[{"name":"Molecular and Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanchen","family":"Wang","sequence":"additional","affiliation":[{"name":"Molecular and Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubai","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunfang","family":"Gu","sequence":"additional","affiliation":[{"name":"Molecular and Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Carr","sequence":"additional","affiliation":[{"name":"Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos M.","family":"Guardia","sequence":"additional","affiliation":[{"name":"Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Shears","sequence":"additional","affiliation":[{"name":"Molecular and Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2106-3102","authenticated-orcid":false,"given":"Robin","family":"Stanley","sequence":"additional","affiliation":[{"name":"Molecular and Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qisheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1358-6309","authenticated-orcid":false,"given":"Raymond D.","family":"Blind","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5920-7784","authenticated-orcid":false,"given":"Xiaoling","family":"Li","sequence":"additional","affiliation":[{"name":"Molecular and Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091804351084000_2026.09.12.751050v1.1","doi-asserted-by":"crossref","unstructured":"Tu-Sekine, B. & Kim, S.F . 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