{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T17:08:17Z","timestamp":1793120897111,"version":"4.5.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"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. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Candida albicans<\/jats:italic>\n                      is a common opportunistic pathogen responsible for both superficial and invasive infections. The unfolded protein response, triggered by endoplasmic reticulum stress, plays a crucial role in its survival and pathogenicity, with the endoplasmic reticulum stress sensor Ire1 serving as a key regulator. Pharmacological inhibition of Ire1 may therefore represent a novel antifungal strategy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted molecular docking to identify small-molecule inhibitors targeting the RNase activity of\n                      <jats:italic>Candida albicans<\/jats:italic>\n                      Ire1, followed by in vitro assays assessing pathogenic traits and in vivo validation using a murine intestinal colonization model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Three candidate inhibitors\u2014MKC8866, STF083010, and 4\u03bc8c\u2014were predicted to interact with Ire1, but only 4\u03bc8c exhibited consistent inhibitory activity. 4\u03bc8c was found to significantly impair key pathogenic traits, including morphological transformation, adhesion, flocculation, and biofilm formation. Additionally, it enhanced the susceptibility of\n                      <jats:italic>Candida albicans<\/jats:italic>\n                      to antifungal drugs and reduced the expression of virulence-related genes. In vivo studies using a murine intestinal colonization model demonstrated that 4\u03bc8c effectively reduced fungal colonization and intestinal tissue damage caused by\n                      <jats:italic>Candida albicans<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These findings demonstrate that pharmacological targeting of the UPR pathway through Ire1 inhibition is feasible. 4\u03bc8c emerges as a promising candidate that diminishes the adaptability and pathogenicity of\n                      <jats:italic>Candida albicans<\/jats:italic>\n                      , offering new insights into antifungal therapeutic development.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2025.1648467","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T05:36:54Z","timestamp":1756877814000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Ire1 inhibitors attenuate Candida albicans pathogenicity and demonstrate potential for application in antifungal therapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Hua","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huihai","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyu","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daxin","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keran","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fukun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"118740","DOI":"10.1016\/j.lfs.2020.118740","article-title":"The molecular mechanism and functional diversity of Upr signaling sensor Ire1","volume":"265","author":"Bashir","year":"2021","journal-title":"Life Sci."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1242\/jeb.088930","article-title":"Stress adaptation in a pathogenic fungus","volume":"217","author":"Brown","year":"2014","journal-title":"J. Exp. Biol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"165rv13","DOI":"10.1126\/scitranslmed.3004404","article-title":"Hidden killers: human fungal infections","volume":"4","author":"Brown","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/s0966-842x(01)02094-7","article-title":"Virulence factors of Candida albicans","volume":"9","author":"Calderone","year":"2001","journal-title":"Trends Microbiol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"4584","DOI":"10.1128\/AAC.00551-15","article-title":"The monoterpene carvacrol generates endoplasmic reticulum stress in the pathogenic fungus Candida albicans","volume":"59","author":"Chaillot","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1080\/21505594.2020.1748930","article-title":"The regulation of hyphae growth in Candida albicans","volume":"11","author":"Chen","year":"2020","journal-title":"Virulence"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.3390\/jof8111130","article-title":"Sterylglucosides in fungi","volume":"8","author":"De Pereira Sa","year":"2022","journal-title":"J. Fungi"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"fuaa060","DOI":"10.1093\/femsre\/fuaa060","article-title":"The impact of the fungus-host-microbiota interplay upon Candida albicans infections: current knowledge and new perspectives","volume":"45","author":"D'enfert","year":"2021","journal-title":"FEMS Microbiol. Rev."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1093\/glycob\/cwn044","article-title":"Protein glycosylation pathways in filamentous fungi","volume":"18","author":"Deshpande","year":"2008","journal-title":"Glycobiology"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"56","DOI":"10.3390\/cells7060056","article-title":"Unfolding the endoplasmic reticulum of a social Amoeba: Dictyostelium discoideum as a new model for the study of endoplasmic reticulum stress","volume":"7","author":"Dominguez-Martin","year":"2018","journal-title":"Cells"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1007\/s12275-016-5621-y","article-title":"Plasma membrane organization promotes virulence of the human fungal pathogen Candida albicans","volume":"54","author":"Douglas","year":"2016","journal-title":"J. Microbiol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1007\/s11046-013-9684-6","article-title":"Hyphae-specific genes Hgc1, Als3, Hwp1, and Ece1 and relevant signaling pathways in Candida albicans","volume":"176","author":"Fan","year":"2013","journal-title":"Mycopathologia"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1126\/science.aap7999","article-title":"Worldwide emergence of resistance to antifungal drugs challenges human health and food security","volume":"360","author":"Fisher","year":"2018","journal-title":"Science"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/B978-0-12-385114-7.00001-5","article-title":"Methods for investigating the Upr in filamentous fungi","volume":"490","author":"Guillemette","year":"2011","journal-title":"Methods Enzymol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"100119","DOI":"10.1016\/j.crmicr.2022.100119","article-title":"Cell death induction in Aspergillus fumigatus: accentuating drug toxicity through inhibition of the unfolded protein response (Upr)","volume":"3","author":"Guirao-Abad","year":"2022","journal-title":"Curr. Res. Microb. Sci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"106","DOI":"10.3390\/cells7080106","article-title":"The unfolded protein response pathway in the yeast Kluyveromyces lactis: a comparative view among yeast species","volume":"7","author":"Hernandez-Elvira","year":"2018","journal-title":"Cells"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1126\/science.1129631","article-title":"Decay of endoplasmic reticulum-localized mrnas during the unfolded protein response","volume":"313","author":"Hollien","year":"2006","journal-title":"Science"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"280","DOI":"10.3389\/fmicb.2016.00280","article-title":"Candida albicans agglutinin-like sequence (Als) family vignettes: a review of Als protein structure and function","volume":"7","author":"Hoyer","year":"2016","journal-title":"Front. 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Fungi"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1080\/21505594.2020.1836902","article-title":"Candida albicans adhesion to central venous catheters: impact of blood plasma-driven germ tube formation and pathogen-derived adhesins","volume":"11","author":"Jung","year":"2020","journal-title":"Virulence"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1477463","DOI":"10.3389\/fcimb","article-title":"The mammalian Ire1 inhibitor, 4micro8C, exhibits broad anti-aspergillus activity in vitro and in a treatment model of fungal keratitis","volume":"14","author":"Kamath","year":"2024","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1128\/EC.00196-13","article-title":"Murine models of Candida gastrointestinal colonization and dissemination","volume":"12","author":"Koh","year":"2013","journal-title":"Eukaryot. Cell"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e35","DOI":"10.1371\/journal.ppat.0040035","article-title":"Mucosal damage and neutropenia are required for Candida albicans dissemination","volume":"4","author":"Koh","year":"2008","journal-title":"PLoS Pathog."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.mib.2020.05.006","article-title":"The gut, the bad and the harmless: Candida albicans as a commensal and opportunistic pathogen in the intestine","volume":"56","author":"Kumamoto","year":"2020","journal-title":"Curr. Opin. Microbiol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"i4","DOI":"10.1093\/jac\/dkx444","article-title":"Changes in the epidemiological landscape of invasive candidiasis","volume":"73","author":"Lamoth","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"110758","DOI":"10.1016\/j.plantsci.2020.110758","article-title":"The two faces of Ire1 and their role in protecting plants from stress","volume":"303","author":"Li","year":"2021","journal-title":"Plant Sci."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"102493","DOI":"10.1016\/j.mib.2024.102493","article-title":"Candida albicans natural diversity: a resource to dissect fungal commensalism and pathogenesis","volume":"80","author":"Lindemann-Perez","year":"2024","journal-title":"Curr. Opin. Microbiol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1080\/21505594.2021.2019950","article-title":"Pathogenesis and virulence of Candida albicans","volume":"13","author":"Lopes","year":"2022","journal-title":"Virulence"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1093\/bfgp\/elu027","article-title":"The importance of connections between the cell wall integrity pathway and the unfolded protein response in filamentous fungi","volume":"13","author":"Malavazi","year":"2014","journal-title":"Brief. Funct. Genomics"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1016\/j.semcdb.2007.09.003","article-title":"The endoplasmic reticulum and the unfolded protein response","volume":"18","author":"Malhotra","year":"2007","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1392606","DOI":"10.3389\/fmicb.2024.1392606","article-title":"A laboratory perspective on Mycobacterium abscessus biofilm culture, characterization and drug activity testing","volume":"15","author":"Meliefste","year":"2024","journal-title":"Front. Microbiol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"5772","DOI":"10.1182\/blood-2011-07-366633","article-title":"Blocksade of Xbp1 splicing by inhibition of Ire1alpha is a promising therapeutic option in multiple myeloma","volume":"119","author":"Mimura","year":"2012","journal-title":"Blood"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"16700","DOI":"10.1038\/srep16700","article-title":"Novel, synergistic antifungal combinations that target translation fidelity","volume":"5","author":"Moreno-Martinez","year":"2015","journal-title":"Sci. Rep."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1146\/annurev-micro-091014-104330","article-title":"Candida albicans biofilms and human disease","volume":"69","author":"Nobile","year":"2015","journal-title":"Ann. Rev. Microbiol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"18026","DOI":"10.1038\/nrdp.2018.26","article-title":"Invasive candidiasis","volume":"4","author":"Pappas","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3109\/10408410903241444","article-title":"Epidemiology of invasive mycoses in North America","volume":"36","author":"Pfaller","year":"2010","journal-title":"Crit. Rev. Microbiol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s00294-023-01263-5","article-title":"Morphogenic plasticity: the pathogenic attribute of Candida albicans","volume":"69","author":"Prasad","year":"2023","journal-title":"Curr. Genet."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1016\/j.cmi.2019.03.028","article-title":"Resistance of Candida to azoles and echinocandins worldwide","volume":"25","author":"Pristov","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1016\/j.chom.2023.02.010","article-title":"One population, multiple lifestyles: commensalism and pathogenesis in the human mycobiome","volume":"31","author":"Proctor","year":"2023","journal-title":"Cell Host Microbe"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"16","DOI":"10.3390\/jof6010016","article-title":"On commensalism of Candida","volume":"6","author":"Romo","year":"2020","journal-title":"J. Fungi"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.ejphar.2018.10.016","article-title":"In silico approaches for screening molecular targets in Candida albicans: a proteomic insight into drug discovery and development","volume":"842","author":"Silva","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"e13307","DOI":"10.1111\/cmi.13307","article-title":"The protein kinase Ire1 impacts pathogenicity of Candida albicans by regulating homeostatic adaptation to endoplasmic reticulum stress","volume":"23","author":"Sircaik","year":"2021","journal-title":"Cell. Microbiol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"Autodock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"E1395","DOI":"10.1073\/pnas.1621188114","article-title":"Targeting Ire1 with small molecules counteracts progression of atherosclerosis","volume":"114","author":"Tufanli","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"2355","DOI":"10.3389\/fmicb.2018.02355","article-title":"Novel combinations of agents targeting translation that synergistically inhibit fungal pathogens","volume":"9","author":"Vallieres","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1111\/cmi.12388","article-title":"Candida albicans colonization and dissemination from the murine gastrointestinal tract: the influence of morphology and Th17 immunity","volume":"17","author":"Vautier","year":"2015","journal-title":"Cell. Microbiol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.mib.2019.04.001","article-title":"Candida albicans biofilm growth and dispersal: contributions to pathogenesis","volume":"52","author":"Wall","year":"2019","journal-title":"Curr. Opin. Microbiol."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: from stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1186\/s40824-023-00443-1","article-title":"Antifungal bio-coating of endotracheal tube built by overexpressing the Mcp1 gene of Saccharomyces boulardii and employing hydrogel as a \"house\" to antagonize Candida albicans","volume":"27","author":"Wei","year":"2023","journal-title":"Biomater. Res."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1016\/j.fgb.2008.06.001","article-title":"Impact of the unfolded protein response upon genome-wide expression patterns, and the role of Hac1 in the polarized growth, of Candida albicans","volume":"45","author":"Wimalasena","year":"2008","journal-title":"Fungal Genet. Biol."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1016\/j.molcel.2022.03.025","article-title":"Reshaping endoplasmic reticulum quality control through the unfolded protein response","volume":"82","author":"Wiseman","year":"2022","journal-title":"Mol. Cell"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"e0227221","DOI":"10.1128\/mBio.02272-21","article-title":"Tunicamycin potentiates antifungal drug tolerance via aneuploidy in Candida albicans","volume":"12","author":"Yang","year":"2021","journal-title":"mBio"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"20221062","DOI":"10.1515\/biol-2022-1062","article-title":"Effects of Ire1 gene on virulence and pathogenicity of Candida albicans","volume":"20","author":"Zhao","year":"2025","journal-title":"Open Life Sci."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1038\/sj.emboj.7600195","article-title":"Hgc1, a novel hypha-specific G1 cyclin-related protein regulates Candida albicans hyphal morphogenesis","volume":"23","author":"Zheng","year":"2004","journal-title":"EMBO J."}],"updated-by":[{"DOI":"10.3389\/fmicb.2025.1721908","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000}}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1648467\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T16:32:44Z","timestamp":1761237164000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1648467\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,3]]},"references-count":57,"alternative-id":["10.3389\/fmicb.2025.1648467"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2025.1648467","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,3]]},"article-number":"1648467"}}