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IL\u201023 receptor (IL\u201023R) signaling holds the potential for promoting neutrophil generation and maturation, yet the underlying mechanisms remain elusive. This study investigates the molecular mechanism and efficacy of Mulberroside C (MC) in alleviating leukopenia via IL\u201023R signaling. In\u00a0vitro, flow cytometry, nitroblue tetrazolium reduction assay, and Giemsa staining were employed to evaluate MC's impact on neutrophil differentiation in NB4 and HL\u201060 cell lines. The antibacterial activity of MC was assessed using an agar plate assay. In\u00a0vivo, leukopenia models induced by irradiation and cyclophosphamide were established in zebrafish and mice to determine MC's effect on neutrophil recovery. Mechanistic studies involved RNA sequencing, network pharmacology analysis, molecular docking, quantitative real\u2010time PCR (qRT\u2010PCR), and Western blotting to explore the associated signaling pathways. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used to identify MC's targets. MC significantly enhanced neutrophil maturation in a dose\u2010dependent manner, facilitating leukopenia recovery. Mechanistically, MC binds to IL\u201023R, upregulating\n                    <jats:italic>G\u2010CSF<\/jats:italic>\n                    ,\n                    <jats:italic>GM\u2010CSF<\/jats:italic>\n                    , and\n                    <jats:italic>RASGRP1<\/jats:italic>\n                    and activating the RAS\/ERK signaling pathway. Notably, the upregulation of\n                    <jats:italic>RASGRP1<\/jats:italic>\n                    by MC supports the generation of fully functional neutrophils, compared to those induced by G\u2010CSF and GM\u2010CSF alone. This study provides the first evidence that MC promotes neutrophil generation and antimicrobial activity through the IL\u201023R\u2010mediated pathway, offering a promising therapeutic strategy for leukopenia.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70026","type":"journal-article","created":{"date-parts":[[2025,7,6]],"date-time":"2025-07-06T20:50:13Z","timestamp":1751835013000},"page":"3578-3600","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>IL<\/scp>\n                    \u201023 Receptor Agonism by Mulberroside C Activates the\n                    <scp>RASGRP1<\/scp>\n                    \/\n                    <scp>RAS<\/scp>\n                    \/\n                    <scp>ERK<\/scp>\n                    Pathway Contributing to Leukopenia 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