{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:28:47Z","timestamp":1787311727524,"version":"build-2736575974"},"reference-count":95,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Nocturnal asthma and airway remodeling are intimately linked to pulmonary circadian dysfunction. The dysregulation of core clock genes (e.g., Bmal1, Rev-erb\u03b1) in macrophages drives metabolic reprogramming and pro-fibrotic signaling. Pharmacological modulation of this clock using natural bioactive compounds offers a promising therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose &amp;amp; scope<\/jats:title>\n                    <jats:p>\n                      This review critically evaluates the\n                      <jats:italic>in vivo<\/jats:italic>\n                      evidence of natural chronobiotics (including resveratrol, quercetin, curcumin, honokiol, and nobiletin) in reshaping the asthmatic microenvironment, specifically focusing on subepithelial fibrosis and airway smooth muscle hyperplasia. We then propose a validation framework to distinguish genuine clock-dependent effects from pleiotropic pharmacological noise.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key challenges<\/jats:title>\n                    <jats:p>\n                      We identify two major translational bottlenecks. First, the \u201cpleiotropy dilemma\u201d: most existing\n                      <jats:italic>in vivo<\/jats:italic>\n                      studies fail to distinguish true clock-dependent modulation from clock-independent antioxidant and anti-inflammatory effects. Second, and more critically, the core clock target BMAL1 itself exhibits a fundamental dichotomy in allergic asthma\u2014myeloid BMAL1 deficiency exacerbates acute eosinophilic inflammation but paradoxically suppresses chronic airway remodeling in a context-dependent manner. This underscores that correlative observations without genetic validation are insufficient, and that chronobiotic efficacy must be rigorously dissected across diverse asthmatic phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Future perspectives<\/jats:title>\n                    <jats:p>To advance respiratory chronopharmacology, we propose a rigorous validation framework requiring macrophage-specific conditional knockout models (e.g., LysM-Cre; Bmal1 fl\/fl). Finally, we highlight the integration of CD206-targeted inhalable nanocarriers, precision chronopharmacological dosing, and spatial transcriptomics as the definitive roadmap to translate natural chronobiotics into disease-modifying therapies for asthma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1922510","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T10:51:45Z","timestamp":1787309505000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural bioactive compounds targeting the macrophage clock in asthma: evidence, challenges, and perspectives"],"prefix":"10.3389","volume":"17","author":[{"given":"Baoyi","family":"Ni","sequence":"first","affiliation":[{"name":"Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Chen","sequence":"additional","affiliation":[{"name":"Hongqi Hospital Affiliated to Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaobin","family":"Sun","sequence":"additional","affiliation":[{"name":"Hongqi Hospital Affiliated to Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhu","family":"Liu","sequence":"additional","affiliation":[{"name":"Hongqi Hospital Affiliated to Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xuyi County People \u2018s Hospital","place":["Huai\u2019 an, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"He","sequence":"additional","affiliation":[{"name":"Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Wang","sequence":"additional","affiliation":[{"name":"Hongqi Hospital Affiliated to Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2018486118","article-title":"The endogenous circadian system worsens asthma at night independent of sleep and other daily behavioral or environmental cycles","volume":"118","author":"Scheer","year":"2021","journal-title":"Proc Natl Acad Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2013-203482","article-title":"The circadian clock and 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