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During the last decade, efficient direct-acting antivirals were introduced into clinical practice. However, clearance of the virus does not reduce the risk of end-stage liver diseases to the level observed in patients who have never been infected. So, investigation of HCV pathogenesis is still warranted. Virus-induced changes in cell metabolism contribute to the development of HCV-associated liver pathologies. Here, we studied the impact of the virus on the metabolism of polyamines and proline as well as on the urea cycle, which plays a crucial role in liver function. It was found that HCV strongly suppresses the expression of arginase, a key enzyme of the urea cycle, leading to the accumulation of arginine, and up-regulates proline oxidase with a concomitant decrease in proline concentrations. The addition of exogenous proline moderately suppressed viral replication. HCV up-regulated transcription but suppressed protein levels of polyamine-metabolizing enzymes. This resulted in a decrease in polyamine content in infected cells. Finally, compounds targeting polyamine metabolism demonstrated pronounced antiviral activity, pointing to spermine and spermidine as compounds affecting HCV replication. These data expand our understanding of HCV\u2019s imprint on cell metabolism.<\/jats:p>","DOI":"10.3390\/cells13121036","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T10:42:34Z","timestamp":1718361754000},"page":"1036","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9704-6977","authenticated-orcid":false,"given":"Natalia F.","family":"Zakirova","sequence":"first","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga A.","family":"Khomich","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"},{"name":"INSERM 1052, CNRS 5286, Centre L\u00e9on B\u00e9rard, Centre de Recherche en Canc\u00e9rologie de Lyon, Universit\u00e9 Claude Bernard Lyon 1, 69434 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga A.","family":"Smirnova","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5447-5253","authenticated-orcid":false,"given":"Jennifer","family":"Molle","sequence":"additional","affiliation":[{"name":"INSERM 1052, CNRS 5286, Centre L\u00e9on B\u00e9rard, Centre de Recherche en Canc\u00e9rologie de Lyon, Universit\u00e9 Claude Bernard Lyon 1, 69434 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3727-2478","authenticated-orcid":false,"given":"Sarah","family":"Duponchel","sequence":"additional","affiliation":[{"name":"INSERM 1052, CNRS 5286, Centre L\u00e9on B\u00e9rard, Centre de Recherche en Canc\u00e9rologie de Lyon, Universit\u00e9 Claude Bernard Lyon 1, 69434 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4660-1322","authenticated-orcid":false,"given":"Dmitry V.","family":"Yanvarev","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir T.","family":"Valuev-Elliston","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, 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Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna L.","family":"Karpenko","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail V.","family":"Golikov","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedric","family":"Bovet","sequence":"additional","affiliation":[{"name":"University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Rindlisbacher","sequence":"additional","affiliation":[{"name":"University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, 3010 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