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The impact of diverse ion channels on macrophage functions and their underlying mechanisms still requires further investigation. In this research, we observed that the expression magnitudes of some ion channels increased under the stimulation of LPS by transcriptomics analysis. Among them, KCNG3 has drawn our attention as it represents a potassium channel subunit with an undefined role in macrophages. To investigate its role, we knocked down KCNG3, resulting in an enhancement of phagocytosis, bactericidal ability, and the expression of pro\u2010inflammatory cytokines, thereby facilitating M1 polarization. Knockdown of KCNG3 led to an increase in potassium ion efflux, an effect that was recapitulated under low potassium conditions, which in turn activated ASK1 and promoted M1 polarization. Through administering inhibitors NQDI\u20101, ASK1 was blocked and reversed the M1 phenotype caused by KCNG3 knockdown. In summary, KCNG3 regulates macrophage polarization via potassium ion flux and ASK1, offering potential for inflammatory disease treatment.<\/jats:p>","DOI":"10.1002\/cbin.70022","type":"journal-article","created":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T08:41:31Z","timestamp":1745224891000},"page":"810-823","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Polarization of Macrophages Regulated by KCNG3 via the Activation of ASK1 Mediated by Potassium Ion Efflux"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9180-6059","authenticated-orcid":false,"given":"Shuting","family":"Zhang","sequence":"first","affiliation":[{"name":"National\u2010Local Joint Engineering Research Center of Biodiagnosis &amp; Biotherapy, The Second Affiliated Hospital Xi'an Jiaotong University Xi'an Shaanxi China"},{"name":"International Joint Research Center on Cell Stress and Disease 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