{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:02:05Z","timestamp":1793142125925,"version":"4.5.0"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["23gm161001h001"],"award-info":[{"award-number":["23gm161001h001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Microbiology and Immunology"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Influenza pneumonia is characterized by excessive inflammatory responses that contribute to severe lung injury and mortality. Supersulfides, endogenously produced cysteine\u2010derived persulfides and polysulfides, exert potent antioxidant, anti\u2010ferroptotic, and anti\u2010inflammatory activities; however, their therapeutic potential after disease onset remains unclear. Here, we investigated the efficacy of\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetylcysteine tetrasulfide (NAC\u2010S2), a highly water\u2010soluble and cell\u2010permeable supersulfide donor, in a mouse model of influenza A virus (IAV)\u2010induced pneumonia. Subcutaneous administration of NAC\u2010S2 rapidly elevated systemic levels of cysteine\u2010 and glutathione\u2010derived supersulfides. In therapeutic treatment starting 2 days post\u2010infection, when body weight loss and clinical signs had already developed, NAC\u2010S2 significantly improved survival and mitigated body weight loss compared with vehicle and oxidized NAC controls. Metabolomic analysis revealed that influenza virus infection depleted lung glutathione persulfide (GSSH), while NAC\u2010S2 effectively restored tissue GSSH levels. NAC\u2010S2 treatment markedly reduced pulmonary interleukin (IL)\u22121\u03b2 and IL\u20106 production without affecting viral load or Type\u2010I interferon responses. Furthermore, NAC\u2010S2 suppressed NLRP3 inflammasome activation and gasdermin D expression, leading to decreased infiltration of CD3\n                    <jats:sup>+<\/jats:sup>\n                    T cells and myeloperoxidase\u2010positive neutrophils. Histopathological analyses confirmed that NAC\u2010S2 ameliorated epithelial injury, interstitial edema, and hemorrhage in infected lungs. Collectively, our findings demonstrate that NAC\u2010S2 exerts therapeutic benefit even after the onset of severe influenza pneumonia, primarily by replenishing supersulfides and alleviating excessive inflammatory responses. Supersulfide donors represent a promising class of adjunctive therapeutics for severe viral pneumonia.\n                  <\/jats:p>","DOI":"10.1111\/1348-0421.70039","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T11:42:28Z","timestamp":1768995748000},"page":"148-159","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Therapeutic Efficacy of the Supersulfide Donor NAC\u2010S2 in Influenza Virus Pneumonia via Suppression of Excessive Inflammatory Responses"],"prefix":"10.1111","volume":"70","author":[{"given":"Foysal","family":"Hossen","sequence":"first","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahisa","family":"Kouwaki","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2074-0597","authenticated-orcid":false,"given":"Yukio","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Department of Cell Pathology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6258-6313","authenticated-orcid":false,"given":"Hiroyasu","family":"Tsutsuki","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan"},{"name":"Department of Clinical Microbiology, Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0543-4006","authenticated-orcid":false,"given":"Tianli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Comprehensive Center for Infectious Disease Control Akita University Graduate School of Medicine Akita Japan"},{"name":"Key Research Laboratory at Akita University Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyu","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azizur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Komohara","sequence":"additional","affiliation":[{"name":"Department of Cell Pathology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1567-8722","authenticated-orcid":false,"given":"Hiroyuki","family":"Oshiumi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7949-7309","authenticated-orcid":false,"given":"Tomohiro","family":"Sawa","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2004.02.017"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01071-08"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2009.11.600"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adq3003"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.70150"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1321232111"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01311-y"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ampbs.2018.01.002"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10091245"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2023.0405"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2019.02.003"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102605"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/10715762.2023.2165918"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2023.102353"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-022-01145-w"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16271"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2024.07.007"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40182-4"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxad057"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103045"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxae040"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1581385"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep41984"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2016-209359"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.02.023"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12985-023-02219-4"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-025-02450-8"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1159\/000543608"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12985-024-02462-3"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1550968"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2025.1605446"},{"key":"e_1_2_11_32_2","doi-asserted-by":"crossref","unstructured":"(b) Erratum in:Frontiers in Cellular and Infection Microbiology15 (August 2024):1691338 https:\/\/doi.org\/10.3389\/fcimb.2025.1691338.","DOI":"10.3389\/fcimb.2025.1691338"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.4MR0616-288R"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2022.10.002"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12459"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-47067-0"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph17010128"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms11010183"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/irv.12171"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2018.01.002"}],"container-title":["Microbiology and Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/1348-0421.70039","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/1348-0421.70039","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/1348-0421.70039","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:37:07Z","timestamp":1772991427000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/1348-0421.70039"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1111\/1348-0421.70039"],"URL":"https:\/\/doi.org\/10.1111\/1348-0421.70039","archive":["Portico"],"relation":{},"ISSN":["0385-5600","1348-0421"],"issn-type":[{"value":"0385-5600","type":"print"},{"value":"1348-0421","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,21]]},"assertion":[{"value":"2025-11-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}