{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:16:55Z","timestamp":1787026615282,"version":"build-2736575974"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"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. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Xiao-Chai-Hu granules (XCHG), a classical traditional Chinese medicine formula derived from the ancient text Erta Treatise on Febrile Diseases, has demonstrated established clinical efficacy in fever management; however, the underlying antipyretic mechanism remains incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study employed an integrated computational-experimental approach combining network pharmacology, molecular docking, molecular dynamics (MD) simulation, and cellular validation to systematically elucidate XCHG\u2019s mechanism of action. Functional validation was performed in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages using nitric oxide (NO) assay, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Through analysis of 18 pharmacokinetically validated blood-absorbed components, we identified 120 fever-related targets, from which 17 core targets and 5 key bioactive compounds (Oroxylin A, Wogonin, Baicalein, Liquiritigenin, and Enoxolone) were screened. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that XCHG modulates inflammation, immune regulation, and key signaling pathways including PI3K-Akt, MAPK, and EGFR tyrosine kinase inhibitor resistance. Molecular docking identified three high-affinity component-target pairs: EGFR-Enoxolone (\u22129.3\u202fkcal\/mol), ESR1-Liquiritigenin (\u22128.7\u202fkcal\/mol), and SRC-Baicalein (\u22128.4\u202fkcal\/mol), with 100-ns MD simulations confirming the structural stability and binding persistence of these complexes. In LPS-stimulated RAW264.7 macrophages, XCHG dose-dependently inhibited NO production and suppressed pro-inflammatory mediators (TNF-\n                      <jats:italic>\u03b1<\/jats:italic>\n                      , IL-6, IL-1\u03b2, PGE2) and enzymes (iNOS, COX-2). Western blot analysis provided direct target validation, demonstrating that XCHG attenuates p-EGFR and p-SRC phosphorylation while restoring ESR1 expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Mechanistically, XCHG exerts comprehensive intervention across the inflammatory-pyrogenic axis through a dual mechanism: upstream blockade of EGFR-SRC signaling coupled with ESR1-mediated immune homeostasis restoration, distinguishing it from conventional single-target antipyretics. This study provides systematic mechanistic insights supporting the evidence-based clinical application of XCHG and establishes a replicable methodological framework for investigating complex herbal formulas.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1772991","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:21:14Z","timestamp":1771564874000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Integrating network pharmacology, molecular docking and dynamics simulation to decipher the antipyretic mechanisms of Xiaochaihu granules"],"prefix":"10.3389","volume":"13","author":[{"given":"Minghe","family":"Gu","sequence":"first","affiliation":[{"name":"The Second Clinical College of Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangzhou Baiyunshan Guanghua Pharmaceutical Co., Ltd.","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Bi","sequence":"additional","affiliation":[{"name":"Guangzhou Baiyunshan Guanghua Pharmaceutical Co., Ltd.","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhui","family":"Situ","sequence":"additional","affiliation":[{"name":"Guangzhou Baiyunshan Guanghua Pharmaceutical Co., Ltd.","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyong","family":"Du","sequence":"additional","affiliation":[{"name":"Guangzhou Baiyunshan Guanghua Pharmaceutical Co., Ltd.","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aihua","family":"Lin","sequence":"additional","affiliation":[{"name":"The Second Clinical College of Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]},{"name":"Guangdong Provincial Hospital of Chinese Medicine-Zhuhai Hospital","place":["Zhuhai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangzhou Baiyunshan Guanghua Pharmaceutical Co., Ltd.","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Liu","sequence":"additional","affiliation":[{"name":"The Second Clinical College of Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]},{"name":"Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome","place":["Guangzhou, 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