{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T12:32:11Z","timestamp":1789561931764,"version":"build-2803163510"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016714","name":"University of Sharjah","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016714","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Severe asthma remains a major unmet clinical challenge, largely due to corticosteroid hyporesponsiveness in a subset of patients. Despite high-dose inhaled or systemic corticosteroids and targeted biologics, chronic airway inflammation often persists, particularly in T helper 2 (Th2)-low, neutrophilic, and mixed inflammatory phenotypes. Corticosteroid failure in severe asthma reflects not only excessive inflammation but a fundamental breakdown of immune regulatory mechanisms. At the molecular level, steroid hyporesponsiveness is associated with impaired glucocorticoid receptor (GR) signaling, including an altered GR\u03b1\/GR\u03b2 balance, sustained activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-\u03baB) pathways, oxidative stress\u2013mediated histone deacetylase 2 (HDAC2) dysfunction, and epigenetic stabilization of pro-inflammatory transcription. Concurrently, regulatory immune networks\u2014particularly regulatory T and B cells that normally enforce immune tolerance and promote inflammatory resolution\u2014are quantitatively and functionally compromised. Although biologics targeting immunoglobulin E (IgE), interleukin-5 (IL-5)\/IL-5 receptor alpha (IL-5R\u03b1), and IL-4 receptor alpha (IL-4R\u03b1) have improved type-2-high asthma, their efficacy in steroid-hyporesponsive disease remains limited, as they do not restore immune regulation or glucocorticoid sensitivity. In this context, IL-35 has emerged as a uniquely positioned immunoregulatory cytokine. Produced mainly by regulatory T and B cells, IL-35 suppresses Th17-driven and innate immune inflammation, inhibits MAPK and NF-\u03baB signaling, expands regulatory immune networks through infectious tolerance, and stabilizes epithelial barrier integrity. Importantly, IL-35 restores corticosteroid sensitivity in experimental models by targeting key drivers of steroid resistance. This review highlights IL-35 as a potential therapeutic target for managing steroid-hyporesponsive severe asthma by linking asthma endotypes, steroid resistance mechanisms, and IL-35 biology.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1790621","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T05:30:39Z","timestamp":1772775039000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Interleukin-35 as a key immunoregulatory mediator in steroid-hyporesponsive severe asthma"],"prefix":"10.3389","volume":"17","author":[{"given":"Jehan","family":"Al-Matouq","sequence":"first","affiliation":[{"name":"Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah","place":["Sharjah, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baraa","family":"Khalid Salah 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