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Two\u2010sample Mendelian randomisation (MR) was conducted to infer causal relationships. Clinical validations utilised peripheral blood neutrophils from UC\u2013IS patients, assessed via western blotting and quantitative real\u2010time polymerase chain reaction (qRT\u2010PCR). The direct binding of ginsenoside Rb1 to annexin A3 (ANXA3) was verified through molecular docking, molecular dynamics simulations and cellular thermal shift assay (CETSA).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      MR analysis indicated a causal association between\n                      <jats:italic>ANXA3<\/jats:italic>\n                      expression and increased risk of IS and UC. Immune infiltration analysis demonstrated a strong positive correlation between\n                      <jats:italic>ANXA3<\/jats:italic>\n                      expression and neutrophil infiltration in both IS and UC. ScRNA\u2010seq confirmed that\n                      <jats:italic>ANXA3<\/jats:italic>\n                      was expressed in neutrophils within diseased tissues. Circulating neutrophils from UC\u2013IS comorbidity patients showed significantly elevated ANXA3 mRNA and protein levels. Molecular dynamics simulations revealed a stable ginsenoside Rb1\u2010ANXA3 complex with favourable binding free energy. CETSA confirmed the direct binding of ginsenoside Rb1 to ANXA3 in primary human neutrophils. UC\u2013IS serum induced neutrophil hyperactivation, including excessive migration, NETosis, myeloperoxidase (MPO) release and reactive oxygen species (ROS) production, which was significantly attenuated by ginsenoside Rb1 in vitro.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>ANXA3 is a predominant neutrophil\u2010derived biomarker linking UC\u2013IS comorbidity. Ginsenoside Rb1 mitigates comorbidity\u2010induced neutrophil hyperactivation by directly binding ANXA3, representing a promising therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70691","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T12:10:27Z","timestamp":1791375027000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010omics and machine learning identify neutrophil annexin A3 as a therapeutic target of ginsenoside Rb1 for comorbidity of ischaemic stroke and ulcerative colitis"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3462-6442","authenticated-orcid":false,"given":"Jiahao","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Mechanism and Quality of Chinese Medicine University of Macau  Macao SAR China"},{"name":"Institute of Chinese Medical Sciences University of Macau  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