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Addressing the urgent need for effective dengue therapeutics, we identified sofalcone, a gastroprotective agent with antioxidant and anti-inflammatory properties, as a potential inhibitor of DENV replication. Sofalcone demonstrated efficacy against all four DENV serotypes, with the dose inhibiting 50% (IC50) value of 28.1 \u00b1 0.42 \u03bcM against viral replication of DENV serotype 2, without significant cytotoxicity. Additionally, sofalcone significantly improved survival rates and reduced viral titers in DENV-infected ICR-suckling mice. Mechanistically, sofalcone induced heme oxygenase-1 (HO-1) expression via the nuclear factor-erythroid 2-reated factor 2 (Nrf2) pathway, which in turn suppressed viral protease activity and restored antiviral interferon (IFN) responses. This included dose-dependent stimulation of IFN downstream antiviral genes such as 2\u2032-5\u2032-oligoadenylate synthetase 1 (OAS1), OAS2, and OAS3. Given its established clinical use as an anti-gastric ulcer drug, sofalcone offers promising potential for rapid application in treating DENV infection.<\/jats:p>","DOI":"10.3390\/ijms26135921","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T05:17:42Z","timestamp":1750396662000},"page":"5921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sofalcone Suppresses Dengue Virus Replication by Activating Heme Oxygenase-1-Mediated Antiviral Interferon Responses"],"prefix":"10.3390","volume":"26","author":[{"given":"Yu-Lun","family":"Ou","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Chun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Hung","family":"Yen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangta","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Kuang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun-Chieh","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8950-064X","authenticated-orcid":false,"given":"Mei-Yueh","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Gangshan Hospital, Kaohsiung 807378, Taiwan"},{"name":"Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0729-9589","authenticated-orcid":false,"given":"Jin-Ching","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan"},{"name":"Department of Biological Sciences, Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan"},{"name":"Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e000530","DOI":"10.1136\/bmjgh-2017-000530","article-title":"Zika, chikungunya and dengue: The causes and threats of new and re-emerging arboviral diseases","volume":"3","author":"Paixao","year":"2018","journal-title":"BMJ Glob. 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