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The cyclic GMP\u2010AMP synthase (cGAS)\u2010stimulator of interferon genes (STING) pathway, activated by cytosolic mitochondrial DNA (mtDNA), has been increasingly implicated in UC. Through proteomics and artificial intelligence modeling, this study identified for the first time that senkyunolide I (SEI), a primary bioactive phthalide from\n                    <jats:italic>Ligusticum striatum<\/jats:italic>\n                    DC. (\n                    <jats:italic>L. striatum<\/jats:italic>\n                    ), inhibits experimental colitis via the cGAS\u2010STING pathway, with mechanistic validation performed in both intestinal tissues and cultured macrophages. Mutagenesis, activity\u2010based protein profiling, and micro\u2010scale thermophoresis reveal that SEI directly binds voltage\u2010dependent anion channel 1 (VDAC1) at residue K12 to inhibit its stress\u2010induced oligomerization. This blockade prevents mtDNA release into the cytosol, thereby suppressing the cGAS\u2010STING cascade and subsequent M1 macrophage polarization, as well as downstream NLRP3 inflammasome activation, pyroptosis, and ferroptosis in macrophages and colon tissues. Overexpression of VDAC1\u2010WT and VDAC1\u2010K12A in mice confirms this mechanism. Clinically, VDAC1 expression in UC patients positively correlates with cGAS\u2010STING activation and disease severity. Collectively, SEI alleviates colitis by targeting VDAC1 oligomerization to inhibit the cGAS\u2010STING pathway in macrophages, establishing the VDAC1\u2010cGAS\u2010STING axis as a promising therapeutic strategy for UC.\n                  <\/jats:p>","DOI":"10.1002\/advs.77045","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T11:52:41Z","timestamp":1786103561000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Senkyunolide I Inhibits mtDNA\u2010cGAS\u2010STING Signaling in Macrophages via Targeting VDAC1 Oligomerization to Attenuate Ulcerative Colitis"],"prefix":"10.1002","author":[{"given":"Zhiming","family":"Ye","sequence":"first","affiliation":[{"name":"Center for Drug Research and Development Guangdong Pharmaceutical University  Guangzhou Guangdong China"},{"name":"Key Laboratory of Pathobiology Ministry of Education Jilin University  Changchun Jilin 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