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This study investigates wedelolactone (WED), a natural coumarin, as a potential therapeutic agent. WED is found to promote neutrophil differentiation and enhance bactericidal function in vitro. Its in vivo efficacy is validated in radiation\u2010induced neutropenic mouse and zebrafish models, where it facilitates rapid recovery of leukocyte and neutrophil levels. An integrated approach using the GEO database, RNA sequencing, molecular docking, and Drug Affinity Responsive Target Stability (DARTS)\u00a0assays identifies TLR2 and its downstream MAPK signaling pathway as essential for WED's anti\u2010neutropenic effects. DARTS confirms significant binding of WED to TLR2. Knockdown of TLR2 with siRNA or inhibition of TLR2 with C29 reduces WED\u2010induced neutrophil differentiation, MEK1\/2 and ERK1\/2 phosphorylation, and expression of transcription factors (PU.1, CEBP\u03b2). Similarly, ERK1\/2 inhibition by SCH772984 impairs WED\u2010induced neutrophil differentiation and bactericidal activity, decreasing PU.1 and CEBP\u03b2 expression without affecting TLR2 levels. These findings position TLR2 as a key therapeutic target for neutropenia, with WED effectively promoting neutrophil differentiation via TLR2 and MEK\/ERK pathway activation. This study highlights the therapeutic potential of targeting TLR2 to alleviate neutropenia and underscores the utility of a multi\u2010omics approach in uncovering drug mechanisms.<\/jats:p>","DOI":"10.1002\/advs.202509807","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T10:43:31Z","timestamp":1766486611000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Wedelolactone, a Novel TLR2 Agonist, Promotes Neutrophil Differentiation and Ameliorates Neutropenia: A Multi\u2010Omics Approach to Unravel the Mechanism"],"prefix":"10.1002","volume":"13","author":[{"given":"Long","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Pharmacy Southwest Medical University  Luzhou Sichuan 646000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of 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