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While ion channels have been implicated in immune cell modulation, how they influence macrophage polarization remains poorly understood. Here, it is demonstrated that ectosomes carrying the ion channel Calhm6 effectively suppress severe inflammation triggered by LPS. These Calhm6\u2010bearing ectosomes, secreted by macrophages, facilitate M2\u2010like polarization, elicit an anti\u2010inflammatory response, and foster immune tolerance. Conversely, Calhm6 deficiency leads to suppressed Creb1 activity, which in turn augments M1\u2010like macrophage polarization, enhancing bactericidal activity and the secretion of pro\u2010inflammatory cytokines. Mechanistically, Chp1 serves as a scaffold protein and undergoes phosphorylation by CaMK4. This phosphorylation enhances the localization of the Calhm6\u2010Chp1\u2010CaMK4 complex to the cell membrane, promoting Creb1 activation and M2\u2010like macrophage polarization calcium\u2010dependently. Moreover, the M1\u2010like polarization inducers LPS and IFN\u03b3 enhance the binding of Irf1 to the Calhm6 promoter, upregulating its expression and stimulating ectosome formation. Conversely, Stat6, activated by IL\u20104, competes with Irf1 for binding to the Calhm6 promoter, thereby suppressing its expression. In summary, our findings unravel the intricate interplay between ion channels, ectosomes, and macrophage polarization, revealing that ectosomal\u2010Calhm6 can serve as a novel therapeutic agent to modulate inflammatory responses and facilitate tissue repair.<\/jats:p>","DOI":"10.1002\/advs.202502395","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T07:39:17Z","timestamp":1758872357000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Calhm6 Governs Macrophage Polarization Through Chp1\u2010Camk4\u2010Creb1 Axis and Ectosomal Delivery in Inflammatory Responses"],"prefix":"10.1002","volume":"13","author":[{"given":"Yanlong","family":"Xin","sequence":"first","affiliation":[{"name":"Department of General Surgery the Second Affiliated Hospital Xi'an Jiaotong University Xi'an 710004 China"},{"name":"National\u2010Local Joint Engineering Research Center of Biodiagnosis &amp; Biotherapy the Second Affiliated Hospital Xi'an Jiaotong University Xi'an 710004 China"},{"name":"International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy the Second Affiliated Hospital Xi'an Jiaotong University Xi'an 710004 China"},{"name":"Precision Medicine Institute the Second Affiliated Hospital Xi'an Jiaotong University Xi'an 710004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of General Surgery the Second Affiliated Hospital Xi'an Jiaotong University Xi'an 710004 China"},{"name":"National\u2010Local Joint Engineering Research Center of Biodiagnosis &amp; 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