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Prominent members of the family\n                    <jats:italic>Flaviviridae<\/jats:italic>\n                    include Dengue virus, Zika virus, and West Nile virus, whose spread has increased globally due to the expansion of their respective mosquito vectors. Despite their importance as a public health concern, there are no FDA\u2010approved antiviral drugs targeting these viruses in humans. One of the viral proteins essential for flavivirus replication is the NS3 protein, a highly conserved multifunctional enzyme implicated in viral polyprotein processing, viral RNA amplification, and modulation of several host cellular processes. In this review, we summarize NS3's functions in the flavivirus life cycle and its impact on clinical outcomes. We also discuss the regulation of NS3 activity through post\u2010translational modifications and highlight ongoing research focused on developing NS3\u2010targeted therapeutic approaches for flavivirus infections.\n                  <\/jats:p>","DOI":"10.1002\/jmv.70878","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:02:54Z","timestamp":1774875774000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Flavivirus NS3 Protein: Its Multifaceted Roles and Therapeutic Potential"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2087-5077","authenticated-orcid":false,"given":"Haejeong","family":"Lee","sequence":"first","affiliation":[{"name":"Florida Research and Innovation Center, Cleveland Clinic Port St. Lucie Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee","family":"Cho","sequence":"additional","affiliation":[{"name":"Florida Research and Innovation Center, Cleveland Clinic Port St. Lucie Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela U.","family":"Gack","sequence":"additional","affiliation":[{"name":"Florida Research and Innovation Center, Cleveland Clinic Port St. Lucie Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-0714-0"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60238-X"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2025.107940"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/13816128113199990635"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2017.33"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00719"},{"key":"e_1_2_10_8_1","first-page":"1101","volume-title":"Wolters Kluwer\/Lippincott Williams & Wilkins Health: Philadelphia, PA","author":"Lindenbach B. 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