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Nevertheless, the epigenetic landscape that orchestrates this antiviral response remains largely elusive. Here, we identify histone demethylase JMJD2D as a critical regulator in defense against IAV infection. A significant upregulation of JMJD2D expression was observed clinically in response to IAV infection, indicating that JMJD2D may play a role in regulating IAV infection. Indeed, JMJD2D-deficient mice exhibit increased susceptibility to IAV, characterized by elevated viral loads, severe lung tissue damage, and reduced survival rates, suggesting that JMJD2D plays an essential role in defense against IAV infection. Consistently, knockdown or pharmacological inhibition of JMJD2D in lung cells suppressed IAV replication and the IAV-triggered innate immune response. Mechanistically, JMJD2D suppressed IAV infection by removing H3K9me3 at the promoter region of retinoic acid inducible gene-I (RIG-I) and cooperating with NF-\u03baB to enhance the expression of RIG-I, a critical sensor for IAV RNA. This study identifies JMJD2D as an epigenetic rheostat that governs RIG-I-mediated antiviral signaling, highlighting its potential as a therapeutic target for mitigating severe IAV infection.<\/jats:p>","DOI":"10.3390\/biom16040604","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T09:37:42Z","timestamp":1776677862000},"page":"604","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Histone Demethylase JMJD2D Suppresses Influenza A Virus Infection by Promoting RIG-I Expression"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8806-2621","authenticated-orcid":false,"given":"Xiaochun","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen 361023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiadi","family":"Liang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanshi","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fudong","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4141-8345","authenticated-orcid":false,"given":"Chundong","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingli","family":"Mo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1465-354X","authenticated-orcid":false,"given":"Yilin","family":"Hong","sequence":"additional","affiliation":[{"name":"Xiamen Key Laboratory of Traditional Chinese Medicine Bio-Engineering, School of Pharmacy, Xiamen Medical College, Xiamen 361023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a038356","DOI":"10.1101\/cshperspect.a038356","article-title":"Human Influenza Epidemiology","volume":"11","author":"Ryu","year":"2021","journal-title":"Cold Spring Harb. 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