{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:06:00Z","timestamp":1792001160988,"version":"4.4.0"},"reference-count":154,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T00:00:00Z","timestamp":1743033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Interferon regulatory factor 5 (IRF5) is a critical transcription factor in the IRF family, playing a pivotal role in modulating immune responses, particularly within the innate immune system. IRF5 regulates the expression of type I interferons (IFNs), proinflammatory cytokines, and other immune-related genes, essential for effective host defense against infections and immune surveillance. Its functions, however, are diverse and highly context-dependent, adapting to different immune challenges and tissue environments. Studies have demonstrated that dysregulated IRF5 activation contributes to the pathogenesis of numerous diseases, including cancer, autoimmune disorders, and chronic inflammatory conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This dysregulation underscores the dual role of IRF5, both in immune protection and in driving pathological inflammation. Given its significant involvement in both physiological and pathological processes, IRF5 presents a promising therapeutic target for managing diseases characterized by excessive inflammation and immune dysregulation. However, developing effective molecules to specifically modulate the IRF5 pathway remains challenging, with limited therapeutic agents available for clinical application. In this review, we examine the diverse roles of IRF5 in various disease contexts, the mechanisms by which IRF5 contributes to disease progression, and the potential therapeutic strategies targeting IRF5. Additionally, we discuss potential complications and risks associated with IRF5-targeted therapies, including the balance between dampening pathological inflammation and preserving essential immune functions. This exploration highlights both the therapeutic potential and the complexity of modulating IRF5 activity in clinical settings.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1535823","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:36:52Z","timestamp":1743122212000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Interferon regulatory factor 5: a potential target for therapeutic intervention in inflammatory diseases"],"prefix":"10.3389","volume":"16","author":[{"given":"Xinyuan","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ata Ur","family":"Rehman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Dang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxing","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Jian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.26.021607.090400","article-title":"The IRF family transcription factors in immunity and oncogenesis","volume":"26","author":"Tamura","year":"2008","journal-title":"Annu Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0378-1119(99)00262-0","article-title":"Interferon regulatory factors: the next generation","volume":"237","author":"Mamane","year":"1999","journal-title":"Gene"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.18.5028","article-title":"Crystal structure of an IRF-DNA complex reveals novel DNA recognition and cooperative binding to a tandem repeat of core sequences","volume":"18","author":"Fujii","year":"1999","journal-title":"EMBO J"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.19.1.623","article-title":"IRF family of transcription factors as regulators of host defense","volume":"19","author":"Taniguchi","year":"2001","journal-title":"Annu Rev Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1080\/08916930701510905","article-title":"The genetics and biology of Irf5-mediated signaling in lupus","volume":"40","author":"Kozyrev","year":"2007","journal-title":"Autoimmunity"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1990","article-title":"IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses","volume":"12","author":"Krausgruber","year":"2011","journal-title":"Nat Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"245804","DOI":"10.1155\/2013\/245804","article-title":"IRF5 is a specific marker of inflammatory macrophages in vivo","volume":"2013","author":"Weiss","year":"2013","journal-title":"Mediators Inflammation"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0103609","article-title":"TRIpartite motif 21 (TRIM21) differentially regulates the stability of interferon regulatory factor 5 (IRF5) isoforms","volume":"9","author":"Lazzari","year":"2014","journal-title":"PloS One"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M500543200","article-title":"Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms. 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