{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T13:49:54Z","timestamp":1784123394242,"version":"3.55.0"},"reference-count":18,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81574099"],"award-info":[{"award-number":["81574099"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Cytokine storm is a critical determinant of mortality in viral pneumonia. The TLR3\u2010NF\u2010\u03baB signaling pathway mediates excessive inflammatory responses, with IL\u20106 as a key effector molecule. This study aimed to identify natural compounds capable of attenuating cytokine storm through modulation of this signaling axis. Network pharmacology was employed to screen active components from Houttuynia cordata and identify therapeutic targets for viral pneumonia. Molecular docking evaluated binding affinities between candidate compounds and core targets. A Poly(I:C)\u2010induced inflammatory model in human bronchial epithelial BEAS\u20102B cells was established to validate protective effects and molecular mechanisms. Post\u2010treatment experiments were conducted to evaluate therapeutic (\n                    <jats:italic>vs.<\/jats:italic>\n                    preventive) efficacy of quercetin. siRNA\u2010mediated knockdown of TLR3 and TRIF was performed to verify pathway dependence. An epithelial\u2010macrophage (BEAS\u20102B\/THP\u20101) co\u2010culture model and primary normal human bronchial epithelial (NHBE) cells were employed to enhance physiological relevance. Cellular thermal shift assay (CETSA) was used to confirm direct target engagement of quercetin with NF\u2010\u03baB p65 and TLR3. Comparative experiments with other Houttuynia cordata flavonoids (isorhamnetin and kaempferol) were conducted to validate the unique contribution of quercetin. Among nine active components of Houttuynia cordata, quercetin exhibited the highest number of targets (142) with 13 intersection genes shared with viral pneumonia disease targets. Molecular docking demonstrated favorable binding of quercetin to NF\u2010\u03baB p65 (\u22127.7\u2009kcal\/mol) and TLR3 (\u22126.3\u2009kcal\/mol). Quercetin dose\u2010dependently restored cell viability, maintained epithelial barrier integrity, inhibited apoptosis, and suppressed IL\u20106, TNF\u2010\u03b1, and IFN\u2010\u03b2 expression. Mechanistically, quercetin inhibited TLR3 and TRIF expression, reduced I\u03baB\u03b1 phosphorylation, blocked p65 nuclear translocation, and decreased p65 binding to the IL6 promoter \u03baB site. Rescue experiments confirmed NF\u2010\u03baB p65 as a key therapeutic target. Post\u2010treatment experiments demonstrated that quercetin administered after Poly(I:C) stimulation (Post\u20100h, Post\u20102h, Post\u20106h) retained significant anti\u2010inflammatory and barrier\u2010protective effects in a time\u2010dependent manner, supporting therapeutic rather than solely preventive efficacy. siRNA knockdown of TLR3 or TRIF abolished Poly(I:C)\u2010induced inflammatory responses and eliminated the additional inhibitory effect of quercetin, genetically confirming pathway dependence. In the BEAS\u20102B\/THP\u20101 co\u2010culture system, epithelial\u2010macrophage crosstalk amplified inflammatory cytokine levels by 2\u20103 fold compared with monoculture, yet quercetin still significantly attenuated this amplified cytokine storm and reversed THP\u20101 M1 polarization. These findings were further validated in primary NHBE cells. CETSA confirmed direct binding of quercetin to p65 (\u0394Tm\u2009=\u2009+4.3\u00b0C) and TLR3 (\u0394Tm\u2009=\u2009+3.3\u00b0C) in intact cells. Comparative experiments showed that quercetin exhibited significantly superior anti\u2010inflammatory efficacy over isorhamnetin and kaempferol at equimolar concentrations. Quercetin attenuates cytokine storm in viral pneumonia through multi\u2010target inhibition of the TLR3\u2010NF\u2010\u03baB\u2010IL\u20106 signaling axis, with both preventive and therapeutic efficacy demonstrated in epithelial monoculture, epithelial\u2010macrophage co\u2010culture, and primary cell models. Genetic knockdown and CETSA experiments provide direct evidence for pathway specificity and target engagement, providing scientific evidence for the clinical application of Houttuynia cordata.\n                  <\/jats:p>","DOI":"10.1002\/jbt.70876","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T06:37:44Z","timestamp":1778481464000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Quercetin Attenuates Cytokine Storm in Viral Pneumonia via Inhibition of the TLR3\u2010NF\u2010\u03baB\u2010IL\u20106 Signaling Axis"],"prefix":"10.1002","volume":"40","author":[{"given":"Yiqun","family":"Zhou","sequence":"first","affiliation":[{"name":"Hepatology and Infectious Diseases Department Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Suzhou Jiangsu China"},{"name":"Hepatology and Infectious Diseases Department Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Nanjing University of Chinese Medicine Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Hepatology and Infectious Diseases Department Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Suzhou Jiangsu China"},{"name":"Hepatology and Infectious Diseases Department Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Nanjing University of Chinese Medicine Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Shen","sequence":"additional","affiliation":[{"name":"Hepatology and Infectious Diseases Department Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Suzhou Jiangsu China"},{"name":"Hepatology and Infectious Diseases Department Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Nanjing University of Chinese Medicine Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8011-1839","authenticated-orcid":false,"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Hepatology and Infectious Diseases Department Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Suzhou Jiangsu China"},{"name":"Hepatology and Infectious Diseases Department Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Nanjing University of Chinese Medicine Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanwu","family":"Lu","sequence":"additional","affiliation":[{"name":"Dermatology Medical Cosmetology Center Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University Ningbo Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rcl.2022.01.010"},{"issue":"18","key":"e_1_2_9_3_1","article-title":"Viral Pneumonia in Immunocompetent Adults]","volume":"183","author":"Clausen C. 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