{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:56:59Z","timestamp":1781672219585,"version":"3.54.5"},"reference-count":116,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"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>Chronic rhinosinusitis (CRS) is a condition with a significant healthcare and economic burden, with a prevalence of 12% in the West. The existing therapies mainly attenuate downstream inflammatory mediators but do not address the underlying immune-regulatory abnormalities that drive disease recurrence and lifelong treatment. Evidence has shown that a regulatory axis involving forkhead box P3 (FOXP3) + regulatory T cells (Tregs), the complement component 5a receptor 1 (C5aR1), and leukemia inhibitory factor (LIF) is crucial for regulating immune tolerance in sinonasal tissues. This review discusses the mechanistic basis for modulating FOXP3, C5aR1, and LIF with natural anti-inflammatory products for the treatment of CRS. A comprehensive literature review across PubMed, Scopus, and Web of Science (2000\u20132026) was conducted to identify research articles on the molecular mechanisms, preclinical evidence, and clinical application of natural compounds in inflammatory disorders and the sinonasal inflammatory pathway. Various studies show that FOXP3+ Tregs are highly depleted in CRS with nasal polyps. Besides, complement signaling via C5aR1 prevents active Treg induction by activating the PI3K-AKT-mTOR pathway. LIF enhances the expression of FOXP3 and opposes Th17 polarization caused by IL-6. Natural products such as epigallocatechin-3-gallate, curcumin, and rosmarinic acid regulate pathways by inhibiting DNA methyltransferases, the complement cascade, and JAK-STAT signaling. Bromelain and cineole have clinical evidence in favor of efficacy in acute sinusitis, and other compounds are showing emerging evidence. The FOXP3-C5aR1-LIF axis is a mechanistic therapeutic target that is largely overlooked by the current biologics. Natural compounds offer potential benefits, including multi-target activity, favorable safety profiles, and the ability to modulate the upstream immune system. Phenotype-based CRS populations should be studied in well-designed trials, bioavailability formulations should be optimized, and synergistic combinations should be systematically explored.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1792658","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:48:17Z","timestamp":1781671697000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Unveiling natural anti-inflammatory compounds for sinusitis treatments by modulating FOXP3, C5aR1, and LIF"],"prefix":"10.3389","volume":"17","author":[{"given":"Chengjian","family":"Cao","sequence":"first","affiliation":[{"name":"Zigong Academy of Medical Sciences, Zigong First People\u2019s Hospital","place":["Zigong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Arefin","family":"Hossen","sequence":"additional","affiliation":[{"name":"Head and Neck Surgery, Otolaryngology. Southwest Medical University Affiliated Hospital","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Sahriyer","family":"Efti","sequence":"additional","affiliation":[{"name":"Oncology, The Research Center for Medicine, Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Warda","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Suez Canal University","place":["Ismailia, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soad K.","family":"AlJaouni","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Pediatric Oncology, Yousef Abdulatif Jameel Scientific Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"ElFar","sequence":"additional","affiliation":[{"name":"Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoxiang","family":"Lv","sequence":"additional","affiliation":[{"name":"Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1398-9995.2011.02646.x","article-title":"Chronic rhinosinusitis in Europe--an underestimated disease. A GA2LEN study","volume":"66","author":"Hastan","year":"2011","journal-title":"Allergy"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2022.01.016","article-title":"Epidemiology of chronic rhinosinusitis: Prevalence and risk factors","volume":"10","author":"Sedaghat","year":"2022","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B3","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1111\/cea.14592","article-title":"Global incidence and prevalence of chronic rhinosinusitis: A systematic review","volume":"55","author":"Min","year":"2025","journal-title":"Clin Exp Allergy"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2335","DOI":"10.1186\/s12889-024-19833-8","article-title":"The impact of chronic diseases on the health-related quality of life of middle-aged and older adults: The role of physical activity and degree of digitization","volume":"24","author":"Hu","year":"2024","journal-title":"BMC Public Health"},{"key":"B5","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-031-77374-7_32","article-title":"Chronic rhinosinusitis","volume-title":"Otolaryngology study guide","author":"Tsetsos","year":"2025"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4193\/Rhin20.600","article-title":"European position paper on rhinosinusitis and nasal polyps 2020","volume":"58","author":"Fokkens","year":"2020","journal-title":"Rhinology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.jaci.2025.02.015","article-title":"New insights into the endotypes of chronic rhinosinusitis in the biologic era","volume":"156","author":"Wang","year":"2025","journal-title":"J Allergy Clin Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/immuno5030026","article-title":"Chronic rhinosinusitis with nasal polyps: Window of immunologic responses and horizon of biological therapies","volume":"5","author":"Farokhi","year":"2025","journal-title":"Immuno"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.iac.2019.12.010","article-title":"The role of allergic rhinitis in chronic rhinosinusitis","volume":"40","author":"Helman","year":"2020","journal-title":"Immunol Allergy Clin North Am"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/surgeries6030048","article-title":"Chronic rhinosinusitis: A multifaceted burden on patients and society\u2014a systematic review","volume":"6","author":"R\u0103deanu","year":"2025","journal-title":"Surgeries"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/falgy.2025.1714577","article-title":"Chronic rhinosinusitis with and without nasal polyps: The state-of-the-art of current treatment strategies and future developments","volume":"6","author":"Nappi","year":"2025","journal-title":"Front Allergy"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1016\/j.jaci.2015.12.1324","article-title":"Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers","volume":"137","author":"Tomassen","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.87674","article-title":"The efficacy and safety of intranasal corticosteroids in chronic rhinosinusitis: A systematic review","volume":"17","author":"Mawkili","year":"2025","journal-title":"Cureus"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/falgy.2025.1573764","article-title":"Efficacy and limitations of systemic corticosteroids in patients with CRSwNP compared to alternative therapies with monoclonal antibodies: Real-life of 101 patients from the Lazio region, Italy","volume":"6","author":"Anastasi","year":"2025","journal-title":"Front Allergy"},{"key":"B15","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.anai.2024.07.001","article-title":"Efficacy of dupilumab for severe chronic rhinosinusitis with nasal polyps and asthma","volume":"133","author":"Tajiri","year":"2024","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/lio2.70282","article-title":"Biologics for chronic rhinosinusitis with nasal polyposis: Current landscape and future directions","volume":"10","author":"Chiu","year":"2025","journal-title":"Laryngoscope Investig Otolaryngol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/life13112165","article-title":"Biologics for chronic rhinosinusitis\u2014a modern option for therapy","volume":"13","author":"Cergan","year":"2023","journal-title":"Life"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2008.02.018","article-title":"T-cell regulation in chronic paranasal sinus disease","volume":"121","author":"Van Bruaene","year":"2008","journal-title":"J Allergy Clin Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nri2343","article-title":"How regulatory T cells work","volume":"8","author":"Vignali","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2010.05.013","article-title":"Migration of regulatory T cells toward airway epithelial cells is impaired in chronic rhinosinusitis with nasal polyposis","volume":"137","author":"Kim","year":"2010","journal-title":"Clin Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0047383","article-title":"Complement defects in patients with chronic rhinosinusitis","volume":"7","author":"Gaunsbaek","year":"2012","journal-title":"PloS One"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/all.12010","article-title":"Role of imbalance of eicosanoid pathways and staphylococcal superantigens in chronic rhinosinusitis","volume":"67","author":"Pezato","year":"2012","journal-title":"Allergy"},{"key":"B23","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.jaci.2016.11.015","article-title":"Classical complement pathway activation in the nasal tissue of patients with chronic rhinosinusitis","volume":"140","author":"Van Roey","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2499","article-title":"Absence of signaling into CD4+ cells via C3aR and C5aR enables autoinductive TGF-\u03b21 signaling and induction of Foxp3+ regulatory T cells","volume":"14","author":"Strainic","year":"2013","journal-title":"Nat Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"86","DOI":"10.3390\/jor3020009","article-title":"The role of leukemia inhibitory factor in counteracting the immunopathology of acute and chronic lung inflammatory diseases","volume":"3","author":"Yu","year":"2023","journal-title":"J Respir"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.4161\/cc.8.9.8348","article-title":"Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6","volume":"8","author":"Gao","year":"2009","journal-title":"Cell Cycle"},{"key":"B27","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1111\/imm.12938","article-title":"The role of transforming growth factor \u03b2 in T helper 17 differentiation","volume":"155","author":"Zhang","year":"2018","journal-title":"Immunology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"7644","DOI":"10.1038\/s41467-025-62628-7","article-title":"Regulatory T cell therapy promotes TGF-\u03b2 and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2","volume":"16","author":"Cheng","year":"2025","journal-title":"Nat Commun"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15252\/embj.201899595","article-title":"STAT 4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation","volume":"38","author":"Zhang","year":"2019","journal-title":"EMBO J"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2300184","article-title":"Disabled C3ar1\/C5ar1 signaling in Foxp3+ T regulatory cells leads to TSDR demethylation and long-term stability","volume":"211","author":"Medof","year":"2023","journal-title":"J Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1321228","article-title":"Beyond FOXP3: A 20-year journey unravelling human regulatory T-cell heterogeneity","volume":"14","author":"Santosh Nirmala","year":"2024","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2024.156557","article-title":"CD4+ Foxp3+ regulatory T-cells in modulating inflammatory microenvironment in chronic rhinosinusitis with nasal polyps: Progress and future prospect","volume":"178","author":"Yusoff","year":"2024","journal-title":"Cytokine"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T cells and immune tolerance","volume":"133","author":"Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/83713","article-title":"The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3","volume":"27","author":"Bennett","year":"2001","journal-title":"Nat Genet"},{"key":"B35","doi-asserted-by":"crossref","DOI":"10.1016\/B978-0-12-374145-5.00250-3","article-title":"FOXO transcription factors","volume-title":"Handbook of cell signaling","author":"Brunet","year":"2010"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nature11581","article-title":"Novel Foxo1-dependent transcriptional programs control Treg cell function","volume":"491","author":"Ouyang","year":"2012","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100004","article-title":"Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells","volume":"207","author":"Harada","year":"2010","journal-title":"J Exp Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2010.7","article-title":"Molecular mechanisms regulating TGF-beta-induced Foxp3 expression","volume":"3","author":"Xu","year":"2010","journal-title":"Mucosal Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20071477","article-title":"The AKT\u2013mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells","volume":"205","author":"Haxhinasto","year":"2008","journal-title":"J Exp Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.05.003","article-title":"Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis","volume":"32","author":"Durant","year":"2010","journal-title":"Immunity"},{"key":"B41","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.anai.2025.04.007","article-title":"Proteomic profiling of nasal fluids and serum for type 2 nasal polyps diagnosis","volume":"135","author":"Hou","year":"2025","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/nu18081274","article-title":"The role of dietary supplements in the treatment of endometriosis: A critical review","volume":"18","author":"W\u00f3jtowicz","year":"2026","journal-title":"Nutrients"},{"key":"B43","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.imlet.2011.04.009","article-title":"Induction of regulatory T cells by green tea polyphenol EGCG","volume":"139","author":"Wong","year":"2011","journal-title":"Immunol Lett"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2019.04.044","article-title":"Epigallocatechin gallate ameliorates airway inflammation by regulating Treg\/Th17 imbalance in an asthmatic mouse model","volume":"72","author":"Yang","year":"2019","journal-title":"Int Immunopharmacol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2021.108920","article-title":"Protective effect of green tea and epigallocatechin-3-gallate in a LPS-induced systemic inflammation model","volume":"101","author":"Azambuja","year":"2022","journal-title":"J Nutr Biochem"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26010229","article-title":"Anti-inflammatory action and mechanisms of resveratrol","volume":"26","author":"Meng","year":"2021","journal-title":"Molecules"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02992","article-title":"Resveratrol attenuates allergic asthma and associated inflammation in the lungs through regulation of miRNA-34a that targets FoxP3 in mice","volume":"9","author":"Alharris","year":"2018","journal-title":"Front Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3390\/molecules31071072","article-title":"Natural modulators of aquaporins in cancer therapy: Functional mechanisms and clinical potential","volume":"31","author":"Ma\u0142kowska","year":"2026","journal-title":"Molecules"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1080\/08916934.2023.2189133","article-title":"Quercetin improves the imbalance of Th1\/Th2 cells and Treg\/Th17 cells to attenuate allergic rhinitis","volume":"56","author":"Ke","year":"2023","journal-title":"Autoimmunity"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.110984","article-title":"Therapeutic effect of berberine on metabolic diseases: Both pharmacological data and clinical evidence","volume":"133","author":"Xu","year":"2021","journal-title":"BioMed Pharmacother"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.18388\/abp.2020_5948","article-title":"Immunomodulatory effects of berberine on Staphylococcus aureus-induced septic arthritis through down-regulation of Th17 and Treg signaling pathways","volume":"69","author":"Asila","year":"2022","journal-title":"Acta Biochim Pol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.fitote.2026.107137","article-title":"From nature to novelty: Enhancing rosmarinic acid\u2019s therapeutic potential through smart molecular design","volume":"190","author":"Leong","year":"2026","journal-title":"Fitoterapia"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/s0006-2952(99)00044-1","article-title":"Inhibition of complement by covalent attachment of rosmarinic acid to activated C3b","volume":"57","author":"Sahu","year":"1999","journal-title":"Biochem Pharmacol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/nu18071032","article-title":"The effects of curcumin on vascular endothelial function, lipid metabolism, inflammation and neuroprotection\u2014a review","volume":"18","author":"Ozorowski","year":"2026","journal-title":"Nutrients"},{"key":"B55","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.anai.2016.09.427","article-title":"Effect of curcumin on nasal symptoms and airflow in patients with perennial allergic rhinitis","volume":"117","author":"Wu","year":"2016","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3390\/biology8030051","article-title":"Curcumin regulates anti-inflammatory responses by JAK\/STAT\/SOCS signaling pathway in BV-2 microglial cells","volume":"8","author":"Porro","year":"2019","journal-title":"Biol (Basel)"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/128.12.2334","article-title":"Green tea polyphenols block endotoxin-induced tumor necrosis factor-production and lethality in a murine model","volume":"128","author":"Yang","year":"1998","journal-title":"J Nutr"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1186\/ar3368","article-title":"Epigallocatechin-3-gallate suppresses the global interleukin-1beta-induced inflammatory response in human chondrocytes","volume":"13","author":"Akhtar","year":"2011","journal-title":"Arthritis Res Ther"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2015.07.001","article-title":"Leukemia inhibitory factor (LIF)","volume":"26","author":"Nicola","year":"2015","journal-title":"Cytokine Growth Fact Rev"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0201595","article-title":"Apigenin alleviates TGF-\u03b21-induced nasal mucosa remodeling by inhibiting MAPK \/ NF-kB signaling pathways in chronic rhinosinusitis","volume":"13","author":"Yang","year":"2018","journal-title":"PloS One"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1177\/1559325820904799","article-title":"Apigenin attenuates allergic responses of ovalbumin-induced allergic rhinitis through modulation of Th1\/Th2 responses in experimental mice","volume":"18","author":"Chen","year":"2020","journal-title":"Dose-Response"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1007\/s12033-024-01269-5","article-title":"Quercetin alleviates the progression of chronic rhinosinusitis without nasal polyps by inhibiting nasal mucosal inflammation and epithelial apoptosis","volume":"67","author":"Meng","year":"2025","journal-title":"Mol Biotechnol"},{"key":"B63","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1136\/bmj.324.7330.144","article-title":"Randomised controlled trial of butterbur and cetirizine for treating seasonal allergic rhinitis","volume":"324","author":"Schapowal","year":"2002","journal-title":"BMJ"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.3390\/medicina57060591","article-title":"Anti-inflammatory and mineralization effects of bromelain on lipopolysaccharide-induced inflammation of human dental pulp cells","volume":"57","author":"Hong","year":"2021","journal-title":"Med (B Aires)"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.3390\/nu16132060","article-title":"Exploring the therapeutic potential of bromelain: Applications, benefits, and mechanisms","volume":"16","author":"Kansakar","year":"2024","journal-title":"Nutrients"},{"key":"B66","article-title":"Therapeutic use, efficiency and safety of the proteolytic pineapple enzyme Bromelain-POS in children with acute sinusitis in Germany","volume":"19","author":"Braun","year":"2005","journal-title":"In Vivo"},{"key":"B67","article-title":"Efficacy and tolerability of bromelain in patients with chronic rhinosinusitis--a pilot study","volume":"9","author":"B\u00fcttner","year":"2013","journal-title":"B-ENT"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.14639\/0392-100X-1693","article-title":"Bromelain\u2019s penetration into the blood and sinonasal mucosa in patients with chronic rhinosinusitis","volume":"38","author":"Passali","year":"2018","journal-title":"Acta Otorhinolaryngol Ital"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.4103\/jpp.JPP_169_16","article-title":"Penetration of bromelain in serum and rhinosinusal mucosa in patients undergoing endoscopic sinus surgery","volume":"8","author":"Passali","year":"2017","journal-title":"J Pharmacol Pharmacother"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3390\/metabo13060751","article-title":"Modes of action of 1,8-cineol in infections and inflammation","volume":"13","author":"Pries","year":"2023","journal-title":"Metabolites"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200404000-00027","article-title":"Therapy for acute nonpurulent rhinosinusitis with cineole: Results of a double-blind, randomized, placebo-controlled trial","volume":"114","author":"Kehrl","year":"2004","journal-title":"Laryngoscope"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.3390\/medicines10060037","article-title":"Rhinosinusitis treatment with cineole: Patient-reported quality of life improvements from a non-interventional, pharmacy-based survey","volume":"10","author":"Werkh\u00e4user","year":"2023","journal-title":"Medicines"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2024.134223","article-title":"Polyphenols: Chemistry, bioavailability, bioactivity, nutritional aspects and human health benefits: A review","volume":"277","author":"El-Saadony","year":"2024","journal-title":"Int J Biol Macromol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1007\/s11694-025-03554-6","article-title":"Polyphenolic nano-encapsulation systems: A review of their formation mechanism, bioavailability, and antioxidant activity","volume":"19","author":"Wang","year":"2025","journal-title":"J Food Meas Charact"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1002\/fft2.533","article-title":"Development and application of polyphenols in food: A comprehensive review","volume":"6","author":"Huang","year":"2025","journal-title":"Food Front"},{"key":"B76","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-030-39855-2_4","article-title":"Pharmacokinetics and bioavailability enhancement of natural products","volume-title":"Natural products for cancer chemoprevention","author":"Phansalkar","year":"2020"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11072078","article-title":"Current understanding of polyphenols to enhance bioavailability for better therapies","volume":"11","author":"Aatif","year":"2023","journal-title":"Biomedicines"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.afres.2025.100730","article-title":"Enhancing the bioaccessibility and stability of curcumin through the formation of curcumin-piperine complexes in delivery systems based on nanoemulsions stabilized with phospholipids and whey protein","volume":"5","author":"Hern\u00e1ndez-Hern\u00e1ndez","year":"2025","journal-title":"Appl Food Res"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2016.11.098","article-title":"Phytosomal curcumin: A review of pharmacokinetic, experimental and clinical studies","volume":"85","author":"Mirzaei","year":"2017","journal-title":"BioMed Pharmacother"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2025.1746176","article-title":"Nanoencapsulation of nutraceuticals: Enhancing stability and bioavailability in functional foods","volume":"12","author":"Hao","year":"2026","journal-title":"Front Nutr"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2025.143630","article-title":"Improving quercetin bioavailability: A systematic review and meta-analysis of human intervention studies","volume":"477","author":"Liu","year":"2025","journal-title":"Food Chem"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.fbio.2024.105352","article-title":"A modified self-micro emulsifying liposome for bioavailability enhancement of quercetin and its biological effects","volume":"62","author":"Lin","year":"2024","journal-title":"Food Biosci"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2025.125584","article-title":"The review of nasal drug delivery system: The strategies to enhance the efficiency of intranasal drug delivery by improving drug absorption","volume":"676","author":"Wei","year":"2025","journal-title":"Int J Pharm"},{"key":"B84","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/B978-0-12-384935-9.10003-3","article-title":"Nasal delivery of peptides and proteins with chitosan and related mucoadhesive polymers","volume-title":"Peptide and protein delivery","author":"Ritthidej","year":"2011"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.3390\/polysaccharides6010006","article-title":"Polysaccharides: New frontiers for nasal administration of medicines","volume":"6","author":"Clementino","year":"2025","journal-title":"Polysaccharides"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2005.07.009","article-title":"Nasal mucoadhesive drug delivery: Background, applications, trends and future perspectives","volume":"57","author":"Ugwoke","year":"2005","journal-title":"Adv Drug Delivery Rev"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics17020207","article-title":"PLGA-based strategies for intranasal and pulmonary applications","volume":"17","author":"Omidian","year":"2025","journal-title":"Pharmaceutics"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13081180","article-title":"Versatile nasal application of cyclodextrins: Excipients and\/or actives","volume":"13","author":"Rassu","year":"2021","journal-title":"Pharmaceutics"},{"key":"B89","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/978-3-031-23112-4_11","article-title":"Novel mucoadhesive polymers for nasal drug delivery","volume-title":"Nasal drug delivery","author":"Djekic","year":"2023"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1002\/clt2.70010","article-title":"Chronic rhinosinusitis with nasal polyps: Key considerations in the multidisciplinary team approach","volume":"15","author":"Pfaar","year":"2025","journal-title":"Clin Transl Allergy"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.2147\/JAA.S321332","article-title":"Intranasal corticosteroids: Topical potency, systemic activity and therapeutic index","volume":"14","author":"Daley-Yates","year":"2021","journal-title":"J Asthma Allergy"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2005.09.048","article-title":"The diagnosis and management of sinusitis: A practice parameter update","volume":"116","author":"Slavin","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1067\/mai.2001.115561","article-title":"Mode of action of intranasal corticosteroids","volume":"108","author":"Mygind","year":"2001","journal-title":"J Allergy Clin Immunol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjoto.2007.11.004","article-title":"Safety of intranasal corticosteroids in acute rhinosinusitis","volume":"29","author":"Demoly","year":"2008","journal-title":"Am J Otolaryngol"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14072487","article-title":"Ocular side effects of dupilumab: A comprehensive overview of the literature","volume":"14","author":"Boscia","year":"2025","journal-title":"J Clin Med"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.88236","article-title":"Safety and efficacy of dupilumab, omalizumab, and mepolizumab in moderate-to-severe asthma: A systematic review","volume":"17","author":"Omar","year":"2025","journal-title":"Cureus"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1186\/s12348-020-00234-y","article-title":"Serum IgE reduction and paradoxical eosinophilia associated with allergic conjunctivitis after dupilumab therapy","volume":"11","author":"Kimura","year":"2021","journal-title":"J Ophthalmic Inflammation Infect"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2023.2251382","article-title":"Post-marketing safety of anti-IL-5 monoclonal antibodies (mAbs): An analysis of the FDA Adverse Event Reporting System (FAERS)","volume":"23","author":"Zou","year":"2024","journal-title":"Expert Opin Drug Saf"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1016\/j.medp.2025.100094","article-title":"Role of natural active pharmaceuticals in the treatment of oral diseases","volume":"2","author":"Wang","year":"2025","journal-title":"Med Plus"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1007\/s11101-025-10194-7","article-title":"Medicinal plants and human health: A comprehensive review of bioactive compounds, therapeutic effects, and applications","volume":"25","author":"Latif","year":"2026","journal-title":"Phytochem Rev"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.156028","article-title":"The molecular basis of the immunomodulatory effects of natural products: A comprehensive review","volume":"135","author":"Beigoli","year":"2024","journal-title":"Phytomedicine"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.4168\/aair.2015.7.6.534","article-title":"Mechanisms of glucocorticoid action in chronic rhinosinusitis","volume":"7","author":"Lee","year":"2015","journal-title":"Allergy Asthma Immunol Res"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1002\/alr.20024","article-title":"Oral corticosteroid therapy in chronic rhinosinusitis without polyposis: A systematic review","volume":"1","author":"Lal","year":"2011","journal-title":"Int Forum Allergy Rhinol"},{"key":"B104","doi-asserted-by":"publisher","first-page":"250186","DOI":"10.1183\/16000617.0186-2025","article-title":"Efficacy of biologic agents in patients with comorbid asthma and chronic rhinosinusitis with nasal polyps: A systematic review and meta-analysis of randomised controlled trials","volume":"35","author":"Kyriakopoulos","year":"2026","journal-title":"Eur Respir Rev"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics12102301","article-title":"Perspectives in therapy of chronic rhinosinusitis","volume":"12","author":"Brzost","year":"2022","journal-title":"Diagnostics"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.75","article-title":"The regulation of immune tolerance by FOXP3","volume":"17","author":"Lu","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aeg4759","article-title":"Foxp3: The epigenetic engineer of regulatory T cell identity","volume":"11","author":"Metzemaekers","year":"2026","journal-title":"Sci Immunol"},{"key":"B108","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1093\/cei\/uxad048","article-title":"Development and function of FOXP3+ regulators of immune responses","volume":"213","author":"Golzari-Sorkheh","year":"2023","journal-title":"Clin Exp Immunol"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-023-00779-2","article-title":"Mechanism of activation and biased signaling in complement receptor C5aR1","volume":"33","author":"Feng","year":"2023","journal-title":"Cell Res"},{"key":"B110","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1007\/978-3-031-94841-1_253","article-title":"Butterbur","volume-title":"Otoneurology and vestibular medicine","author":"Cherchi","year":"2025"},{"key":"B111","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.3390\/proceedings2024102054","article-title":"Assessment of the chemical hazards in herbs consumed in Europe: Toxins, heavy metals, and pesticide residues","volume-title":"IECTO 2024","author":"Carpena","year":"2024"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.3390\/nu14112329","article-title":"New mechanisms of bromelain in alleviating non-alcoholic fatty liver disease-induced deregulation of blood coagulation","volume":"14","author":"Hu","year":"2022","journal-title":"Nutrients"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-025-03920-5","article-title":"Metabolic insights into drug absorption: Unveiling piperine\u2019s transformative bioenhancing potential","volume":"42","author":"Tripathi","year":"2025","journal-title":"Pharm Res"},{"key":"B114","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s12906-016-1079-z","article-title":"Safety classification of herbal medicines used in pregnancy in a multinational study","volume":"16","author":"Kennedy","year":"2016","journal-title":"BMC Complem Altern Med"},{"key":"B115","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1007\/s11882-017-0690-5","article-title":"Economics of chronic rhinosinusitis","volume":"17","author":"Rudmik","year":"2017","journal-title":"Curr Allergy Asthma Rep"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1002\/lary.32063","article-title":"Spending and utilization for chronic rhinosinusitis with nasal polyps therapies among commercially insured beneficiaries","volume":"135","author":"Bhat","year":"2025","journal-title":"Laryngoscope"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1792658\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:48:23Z","timestamp":1781671703000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1792658\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":116,"alternative-id":["10.3389\/fimmu.2026.1792658"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1792658","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]},"article-number":"1792658"}}