{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T04:59:15Z","timestamp":1780981155045,"version":"3.54.1"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"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":"\n Chelerythrine is a natural benzophenanthridine alkaloid with various pharmacological activities. However, whether Chelerythrine can influence innate immunity and its underlying molecular mechanisms remain unclear. In this study, we found that 10 \u03bcM Chelerythrine significantly extended the lifespan of\n Caenorhabditis elegans<\/jats:italic>\n infected with\n Candida albicans<\/jats:italic>\n (\n C. albicans<\/jats:italic>\n ) and inhibited the proliferation of\n C. albicans<\/jats:italic>\n . This enhanced host resistance to infection was not achieved by reducing the intestinal fungal burden. Transcriptomic sequencing analysis revealed that Chelerythrine activates the FoxO and Fatty acid metabolism pathways in\n C. elegans<\/jats:italic>\n . Interestingly, the lifespan-extending effect of Chelerythrine was completely abolished in\n daf-16<\/jats:italic>\n and\n nhr-49<\/jats:italic>\n mutants. Similarly, mutations in the fatty acid desaturase genes\n fat-5<\/jats:italic>\n ,\n fat-6<\/jats:italic>\n , and\n fat-7<\/jats:italic>\n also blocked this protective effect. RT-qPCR results confirmed that Chelerythrine treatment significantly upregulated the expression of FoxO pathway downstream genes (\n sod-3<\/jats:italic>\n ,\n thn-2<\/jats:italic>\n ,\n lys-7<\/jats:italic>\n ) and fatty acid metabolism-related genes (\n nhr-49<\/jats:italic>\n ,\n mdt-15<\/jats:italic>\n ,\n fat-5<\/jats:italic>\n ,\n fat-6<\/jats:italic>\n ,\n fat-7<\/jats:italic>\n ). Fluorescent reporter gene assays further demonstrated that Chelerythrine promotes the nuclear localization of DAF-16::GFP and enhances the fluorescence expression of SOD-3::GFP, FAT-5::GFP, FAT-6::GFP, and FAT-7::GFP. Additionally, broad-spectrum antibacterial assays showed that 10 \u03bcM Chelerythrine had no direct inhibitory activity against various pathogens, including\n Listeria monocytogenes<\/jats:italic>\n ,\n Enterococcus faecalis<\/jats:italic>\n ,\n Pseudomonas aeruginosa<\/jats:italic>\n , and\n Salmonella enterica<\/jats:italic>\n , indicating that it does not enhance host immunity by directly suppressing pathogen growth. In summary, this study demonstrates that Chelerythrine enhances the innate immune response of\n C. elegans<\/jats:italic>\n against\n C. albicans<\/jats:italic>\n by activating the DAF-16\/FoxO pathway and the NHR-49-mediated fatty acid metabolism pathway. Our work reveal that Chelerythrine is a potential therapeutic candidate for the treatment of\n C. albicans<\/jats:italic>\n infections.\n <\/jats:p>","DOI":"10.3389\/fimmu.2026.1828802","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T04:29:38Z","timestamp":1780979378000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Chelerythrine enhances anti-fungi immunity in Caenorhabditis elegans via DAF-16 and NHR-49 mediated fatty acid metabolism"],"prefix":"10.3389","volume":"17","author":[{"given":"Shenyuan","family":"Fan","sequence":"first","affiliation":[{"name":"Key Laboratory of Oral Disease Research of the Education Department of Guizhou Province, School of Stomatology, Zunyi Medical University","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohui","family":"Bai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Oral Disease Research of the Education Department of Guizhou Province, School of Stomatology, Zunyi Medical University","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Zhong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Oral Disease Research of the Education Department of Guizhou Province, School of Stomatology, Zunyi Medical University","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xiao","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Pharmaceutical Research for Tumor Prevention and Treatment of the Education Department of Guizhou Province, Zunyi Medical University","place":["Zunyi, Guizhou, China"]},{"name":"College of Basic Medicine, Zunyi Medical University","place":["Zunyi, Guizhou, China"]},{"name":"Institute of Life Sciences, Zunyi Medical University","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Tian","sequence":"additional","affiliation":[{"name":"Key Laboratory of Oral Disease Research of the Education Department of Guizhou Province, School of Stomatology, Zunyi Medical University","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034515625222","article-title":"Innate immunity and saliva in candida albicans\u2013mediated oral diseases","volume":"95","author":"Salvatori","year":"2016","journal-title":"J Dent Res"},{"key":"B2","doi-asserted-by":"publisher","first-page":"18026","DOI":"10.1016\/j.idc.2006.07.004","article-title":"Invasive candidiasis","volume":"4","author":"Pappas","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1038\/s41598-017-01123-6","article-title":"Clinical and microbiological characteristics, and impact of therapeutic strategies on the outcomes of children with candidemia","volume":"7","author":"Tsai","year":"2017","journal-title":"Sci Rep"},{"key":"B4","doi-asserted-by":"publisher","first-page":"5352","DOI":"10.1038\/s41467-022-32249-5","article-title":"The importance of antimicrobial resistance in medical mycology","volume":"13","author":"Gow","year":"2022","journal-title":"Nat Commun"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00720-1","article-title":"Tackling the emerging threat of antifungal resistance to human health","volume":"20","author":"Fisher","year":"2022","journal-title":"Nat Rev Microbiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1128\/mmbr.00021-23","article-title":"Candida albicans and candida glabrata: global priority pathogens","volume":"88","author":"Katsipoulaki","year":"2024","journal-title":"Microbiol Mol Biol Reviews: MMBR"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002074","article-title":"Candida albicans infection of caenorhabditis elegans induces antifungal immune defenses","volume":"7","author":"Pukkila-Worley","year":"2011","journal-title":"PloS Pathog"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1186\/s12967-025-07025-w","article-title":"Chelerythrine inhibits esophageal squamous cell carcinoma progression via PINK1-parkin-mediated mitophagy","volume":"23","author":"Zhou","year":"2025","journal-title":"J Transl Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.colsurfb.2020.111003","article-title":"Anti-microbial and anti-biofilm activities of combined chelerythrine-sanguinarine and mode of action against candida albicans and cryptococcus neoformans in vitro","volume":"191","author":"Qian","year":"2020","journal-title":"Colloids Surfaces B Biointerfaces"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.pestbp.2020.01.007","article-title":"In vitro antifungal activity and possible mechanisms of action of chelerythrine","volume":"164","author":"Wei","year":"2020","journal-title":"Pestic Biochem Physiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2023.105732","article-title":"Chelerythrine chloride inhibits zika virus infection by targeting the viral NS4B protein","volume":"219","author":"Loe","year":"2023","journal-title":"Antiviral Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2022.120358","article-title":"Chelerythrine inhibits the progression of glioblastoma by suppressing the TGFB1-ERK1\/2\/Smad2\/3-snail\/ZEB1 signaling pathway","volume":"293","author":"Zhu","year":"2022","journal-title":"Life Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2022.154140","article-title":"Chelerythrine ameliorates rheumatoid arthritis by modulating the AMPK\/mTOR\/ULK-1 signaling pathway","volume":"104","author":"Cai","year":"2022","journal-title":"Phytomed: Int J Phytotherapy Phytopharmacol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1093\/oxfordjournals.bmb.a071019","article-title":"The genetics of Caenorhabditis elegans","volume":"77","author":"Brenner","year":"1974","journal-title":"Genetics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00430-019-00635-4","article-title":"Caenorhabditis elegans as a model animal for investigating fungal pathogenesis","volume":"209","author":"Madende","year":"2020","journal-title":"Med Microbiol Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0030018","article-title":"Antifungal chemical compounds identified using a C. elegans pathogenicity assay","volume":"3","author":"Breger","year":"2007","journal-title":"PloS Pathog"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.5c08997","article-title":"Luteolin decreases fat accumulation and extends lifespan in caenorhabditis elegans via DAF-16\/FOXO and NHR-49\/PPAR-\u03b1","volume":"73","author":"Liu","year":"2025","journal-title":"J Agric Food Chem"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jff.2025.106708","article-title":"Ginkgolide B promotes fat-lowering and lifespan in caenorhabditis elegans via DAF-2\/DAF-16 signaling pathway","volume":"126","author":"Zhang","year":"2025","journal-title":"J Funct Foods"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106265","article-title":"Dioscin integrates regulation of monosaturated fatty acid metabolism to extend the life span through XBP-1\/SBP-1 dependent manner","volume":"26","author":"Xiao","year":"2023","journal-title":"iScience"},{"key":"B20","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1007\/s00018-023-04970-x","article-title":"The homeodomain transcription factor CEH-37 regulates PMK-1\/p38 MAPK pathway to protect against intestinal infection via the phosphatase VHP-1","volume":"80","author":"Liu","year":"2023","journal-title":"Cell Mol Life Sci: CMLS"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiad294","article-title":"Dioscin activates endoplasmic reticulum unfolded protein response for defense against pathogenic bacteria in caenorhabditis elegans via IRE-1\/XBP-1 pathway","volume":"229","author":"Xiao","year":"2024","journal-title":"J Infect Dis"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.109679","article-title":"Luteolin promotes pathogen resistance in caenorhabditis elegans via DAF-2\/DAF-16 insulin-like signaling pathway","volume":"115","author":"Xiao","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-024-01434-3","article-title":"DEAD-box RNA helicase DDX-23 mediates dietary restriction induced health span in caenorhabditis elegans","volume":"47","author":"Xiao","year":"2025","journal-title":"GeroScience"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007893","article-title":"The fatty acid oleate is required for innate immune activation and pathogen defense in caenorhabditis elegans","volume":"15","author":"Anderson","year":"2019","journal-title":"PloS Pathog"},{"key":"B25","article-title":"Delta-9 fatty acid desaturase mutants display increased body size","author":"Clark","year":"2018","journal-title":"microPub Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nature04942","article-title":"An ARC\/mediator subunit required for SREBP control of cholesterol and lipid homeostasis","volume":"442","author":"Yang","year":"2006","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.111472","article-title":"Schisandrin a enhances pathogens resistance by targeting a conserved p38 MAPK pathway","volume":"128","author":"Xiao","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2004.07.022","article-title":"The ERK MAP kinase cascade mediates tail swelling and a protective response to rectal infection in C. elegans","volume":"14","author":"Nicholas","year":"2004","journal-title":"Curr Biol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1080\/21505594.2019.1706305","article-title":"Metformin promotes innate immunity through a conserved PMK-1\/p38 MAPK pathway","volume":"11","author":"Xiao","year":"2020","journal-title":"Virulence"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.5c09928","article-title":"Ursolic acid activates mitochondrial unfolded protein response to enhance innate immunity via transcription factor ATFS-1\/ATF5","volume":"73","author":"Xiong","year":"2025","journal-title":"J Agric Food Chem"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1039\/d5fo03539b","article-title":"Mitochondrial UPR is required for resveratrol mediated anti-bacterial immunity","volume":"16","author":"Zhang","year":"2025","journal-title":"Food Funct"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodres.2025.118231","article-title":"Aspartame enhances innate immunity and extends lifespan in caenorhabditis elegans via autophagy pathway","volume":"227","author":"Han","year":"2026","journal-title":"Food Res Int"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2014.1000752","article-title":"Looking into candida albicans infection, host response, and antifungal strategies","volume":"6","author":"Wang","year":"2015","journal-title":"Virulence"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-99-8929-4_3","article-title":"GABAergic synapses suppress intestinal innate immunity via insulin signaling in caenorhabditis elegans","volume":"118","author":"Zheng","year":"2021","journal-title":"PNAS"},{"key":"B35","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nri2689","article-title":"Evolution of host innate defence: insights from caenorhabditis elegans and primitive invertebrates","volume":"10","author":"Irazoqui","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2025.03.011","article-title":"Chrysophanol delays aging via insulin\/IGF-1 signaling pathway","volume":"232","author":"Zhang","year":"2025","journal-title":"Free Radical Biol Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2025.103992","article-title":"The 1 -cys peroxiredoxin, PRDX-6, suppresses an NHR-49-dependent pro-survival response, including the flavin monooxygenase, FMO-2, that protects against fungal and bacterial infection","volume":"91","author":"Button","year":"2025","journal-title":"Redox Biol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/8496063","article-title":"Pioglitazone hydrochloride extends the lifespan of caenorhabditis elegans by activating DAF-16\/FOXO- and SKN-1\/NRF2-related signaling pathways","volume":"2022","author":"Jia","year":"2022","journal-title":"Oxid Med Cell Longevity"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.103874","article-title":"Sanguinarine promotes healthspan and innate immunity through a conserved mechanism of ROS-mediated PMK-1\/SKN-1 activation","volume":"25","author":"Liu","year":"2022","journal-title":"iScience"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2022.109385","article-title":"Brevilin a enhances innate immunity and the resistance of oxidative stress in caenorhabditis elegans via p38 MAPK pathway","volume":"113","author":"Zhu","year":"2022","journal-title":"Int Immunopharmacol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2023.102285","article-title":"Protocol for assessing the healthspan of caenorhabditis elegans after potential anti-aging drug treatment","volume":"4","author":"Xiao","year":"2023","journal-title":"STAR Protoc"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.105539","article-title":"Usnic acid extends healthspan and improves the neurodegeneration diseases via mTOR\/PHA-4 signaling pathway in caenorhabditis elegans","volume":"25","author":"Xiao","year":"2022","journal-title":"iScience"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13567","article-title":"Metformin induces S-adenosylmethionine restriction to extend the caenorhabditis elegans healthspan through H3K4me3 modifiers","volume":"21","author":"Xiao","year":"2022","journal-title":"Aging Cell"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxrep.2021.06.007","article-title":"Impact of drug solvents on C. elegans pharyngeal pumping","volume":"8","author":"Calahorro","year":"2021","journal-title":"Toxicol Rep"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1177\/1753425917732822","article-title":"PKA\/KIN-1 mediates innate immune responses to bacterial pathogens in caenorhabditis elegans","volume":"23","author":"Xiao","year":"2017","journal-title":"Innate Immun"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.111837","article-title":"S-adenosylmethionine (SAM) diet promotes innate immunity via histone H3K4me3 complex","volume":"131","author":"Xiao","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2025.108318","article-title":"Asperuloside promotes innate immunity via IRE-1\/XBP-1 mediated unfolded protein response","volume":"157","author":"Zhou","year":"2025","journal-title":"Bioorg Chem"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1012225","article-title":"Biofilm-associated metabolism via ERG251 in candida albicans","volume":"20","author":"Xiong","year":"2024","journal-title":"PloS Pathog"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms11081929","article-title":"Escherichia coli nissle 1917 antagonizes candida albicans growth and protects intestinal cells from C. albicans-mediated damage","volume":"11","author":"Rebai","year":"2023","journal-title":"Microorganisms"},{"key":"B50","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1007\/s00018-025-05869-5","article-title":"Ginkgolide a enhances the resistance to pathogen infection through mitochondrial unfolded protein response","volume":"82","author":"Cui","year":"2025","journal-title":"Cell Mol Life Sci: CMLS"},{"key":"B51","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1186\/s12964-025-02386-7","article-title":"Parental S-adenosylmethionine diet defines offspring immune response via histone H3K4me3 complex and endoplasmic reticulum UPR","volume":"23","author":"Liu","year":"2025","journal-title":"Cell Commun Signaling"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00494-23","article-title":"Caffeic acid activates mitochondrial UPR to resist pathogen infection in caenorhabditis elegans via the transcription factor ATFS-1","volume":"92","author":"Xiao","year":"2024","journal-title":"Infect Immun"},{"key":"B53","doi-asserted-by":"publisher","first-page":"5508","DOI":"10.1038\/s41598-025-90255-1","article-title":"Chlorogenic acid inhibits pseudomonas toxin pyocyanin and activates mitochondrial UPR to protect host against pathogen infection","volume":"15","author":"Xiao","year":"2025","journal-title":"Sci Rep"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1126\/science.1203411","article-title":"Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes","volume":"332","author":"Sun","year":"2011","journal-title":"Science"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.crfs.2025.101299","article-title":"Parental sodium benzoate diet induces fat accumulation in offspring via histone H3K9me3 and SKN-1\/Nrf2","volume":"12","author":"Fan","year":"2026","journal-title":"Curr Res Food Sci"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-00630-w","article-title":"The cAMP-PKA pathway-mediated fat mobilization is required for cold tolerance in C. elegans","volume":"7","author":"Liu","year":"2017","journal-title":"Sci Rep"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1536143","article-title":"Berberine hydrochloride enhances innate immunity to protect against pathogen infection via p38 MAPK pathway","volume":"16","author":"Xiao","year":"2025","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1828802\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T04:29:44Z","timestamp":1780979384000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1828802\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,9]]},"references-count":57,"alternative-id":["10.3389\/fimmu.2026.1828802"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1828802","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,9]]},"article-number":"1828802"}}