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Here, we show that ancestral SARS-CoV-2, Delta, or Omicron BA.5 variants replicate most efficiently at 37\u00b0C. We found that transient receptor potential vanilloid 4 (TRPV4)-mediated calcium influx, a thermosensitive cation channel known to be activated at 37\u00b0C, contributes to efficient SARS-CoV-2 replication. In addition, a calcineurin inhibitor, cyclosporine A (Cys A), and manidipine, an FDA-approved calcium channel blocker, both suppressed viral replication and protected Syrian hamsters from lethal infection with the SARS-CoV-2 Delta variant. Notably, a selective TRPV4 antagonist also conferred protection in infected hamsters. These results suggest that TRPV4-mediated calcium influx contributes to efficient SARS-CoV-2 replication at 37\u00b0C and highlight manidipine as a strong candidate for repurposing as an anti-SARS-CoV-2 therapeutic.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014520","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T17:45:56Z","timestamp":1787334356000},"page":"e1014520","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["TRPV4-mediated calcium influx contributes temperature-dependent SARS-CoV-2 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