{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:58:58Z","timestamp":1791392338222,"version":"4.3.3"},"reference-count":45,"publisher":"National Academy of Sciences","issue":"41","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,13]]},"abstract":"<jats:p>Severe mpox virus (MPXV) infection causes immunopathological manifestations in patients. Here, we provide clinical evidence of MPXV-induced inflammation in a large patient cohort and demonstrate direct macrophage infection in skin tissues from an autopsied mpox patient. In human macrophages, MPXV efficiently enters, replicates, and produces infectious particles. Infection activates both AIM2 and NLRP3 inflammasomes, triggering inflammatory responses and three forms of programmed cell death: pyroptosis, apoptosis, and necroptosis. Inflammasome inhibition reduces MPXV-induced inflammation and cell death without affecting viral replication. Screening clinically used anti-inflammatory drugs identified flufenamic acid, which suppresses MPXV-induced inflammation and cell death and, unexpectedly, also inhibits viral infection. Combined treatment with flufenamic acid and the antiviral brincidofovir further enhances suppression of viral infection, inflammatory response, and cell death, while largely preventing MPXV-induced transcriptomic reprogramming in macrophages. These effects were consistent across clade IIb, Ia, and Ib strains associated with the 2022\u20132023 global and recent African outbreaks. Together, our findings provide insight into MPXV immunopathology and support multitarget therapeutic strategies for severe mpox.<\/jats:p>","DOI":"10.1073\/pnas.2623018123","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:35:51Z","timestamp":1791390951000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Infection of macrophages by mpox virus activates inflammasome and cell death, informing multitarget therapeutic strategies"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0557-7215","authenticated-orcid":false,"given":"Yining","family":"Wang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03dnytd23","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Sciences and Biopharmaceutical Sciences, Shenyang Pharmaceutical University","place":["Shenyang 110016, China"]},{"name":"Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center","place":["Rotterdam 3015GD, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8307-7991","authenticated-orcid":false,"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center","place":["Rotterdam 3015GD, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theano","family":"Tsikari","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05xvt9f17","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anatomy and Embryology, Leiden University Medical Center","place":["Leiden 2333ZA, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University","place":["Xuzhou 221004, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1976-6400","authenticated-orcid":false,"given":"Fangfang","family":"Chang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049tv2d57","id-type":"ROR","asserted-by":"publisher"}],"name":"Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People\u2019s Hospital, Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology","place":["Shenzhen 518112, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuxiang","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049tv2d57","id-type":"ROR","asserted-by":"publisher"}],"name":"Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People\u2019s Hospital, Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology","place":["Shenzhen 518112, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7554-0894","authenticated-orcid":false,"given":"Ana Maria Gon\u00e7alves","family":"da Silva","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036rp1748","id-type":"ROR","asserted-by":"publisher"}],"name":"Departamento de Patologia, Faculdade de Medicina, Universidade de S\u00e3o Paulo","place":["S\u00e3o Paulo 05508\u2011220, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1100-0982","authenticated-orcid":false,"given":"Rick","family":"Schraauwen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC-University Medical Center","place":["Rotterdam 3015GD, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dewy Mae","family":"Offermans","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center","place":["Rotterdam 3015GD, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijin","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049tv2d57","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Southern University of Science and Technology","place":["Shenzhen 518055, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry L. A.","family":"Janssen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center","place":["Rotterdam 3015GD, The Netherlands"]},{"id":[{"id":"https:\/\/ror.org\/03dbr7087","id-type":"ROR","asserted-by":"publisher"}],"name":"Toronto Center for Liver Disease, Toronto General Hospital, University of Toronto","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6436-4573","authenticated-orcid":false,"given":"Pengfei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center","place":["Rotterdam 3015GD, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7330-262X","authenticated-orcid":false,"given":"Wenshi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University","place":["Xuzhou 221004, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria V.","family":"Orlova","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05xvt9f17","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anatomy and Embryology, Leiden University Medical Center","place":["Leiden 2333ZA, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6659-7186","authenticated-orcid":false,"given":"Amaro","family":"Nunes Duarte-Neto","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036rp1748","id-type":"ROR","asserted-by":"publisher"}],"name":"Departamento de Patologia, Faculdade de Medicina, Universidade de S\u00e3o Paulo","place":["S\u00e3o Paulo 05508\u2011220, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049tv2d57","id-type":"ROR","asserted-by":"publisher"}],"name":"Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People\u2019s Hospital, Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology","place":["Shenzhen 518112, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9982-6184","authenticated-orcid":false,"given":"Qiuwei","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center","place":["Rotterdam 3015GD, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00152-25"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)02353-5"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00273-8"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.15336"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2412439"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104424"},{"key":"e_1_3_4_7_2","first-page":"4359","article-title":"Pathogenesis of fulminant monkeypox with bacterial sepsis after experimental infection with West African monkeypox virus in a cynomolgus monkey","volume":"7","author":"Nagata N.","year":"2014","unstructured":"N. Nagata , Pathogenesis of fulminant monkeypox with bacterial sepsis after experimental infection with West African monkeypox virus in a cynomolgus monkey. Int. J. Clin. Exp. Pathol. 7, 4359\u20134370 (2014).","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2014.12.001"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0331-4"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3780373"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-01107-9"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2022.101100"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adp8170"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adn0178"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(23)00574-1"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpsc.108"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2023.12.086"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae973"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature15514"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2023.105674"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105254"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(22)00662-4"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02075-X"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00775-4"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-023-01489-6"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-023-00545-z"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02314"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2315653121"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-025-02579-6"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.03.040"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202250235"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00822-2"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2023.10.001"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021436"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00793-7"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2012.67"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(22)00876-3"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2013.01.012"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01307-2"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2506495"},{"key":"e_1_3_4_41_2","unstructured":"Medscape Brincidofovir. (https:\/\/reference.medscape.com\/drug\/tembexa-brincidofovir-4000173#0)."},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12504"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107631"},{"key":"e_1_3_4_44_2","unstructured":"Y. Wang Data from \u201cRNA seq data for MPXV macrophahes.\u201d Mendeley Data. https:\/\/data.mendeley.com\/datasets\/yb6gv2dk66\/1. Deposited 30 October 2025."},{"key":"e_1_3_4_45_2","unstructured":"Y. Wang Data from \u201cMPXV inflammation final data.\u201d Mendeley Data. https:\/\/data.mendeley.com\/datasets\/mj4j8vsp8z\/1. Deposited 11 September 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2623018123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:35:55Z","timestamp":1791390955000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2623018123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":45,"journal-issue":{"issue":"41","published-print":{"date-parts":[[2026,10,13]]}},"alternative-id":["10.1073\/pnas.2623018123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2623018123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]},"assertion":[{"value":"2026-07-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2623018123"}}