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This study was conducted to investigate the radiosensitizing effects of Sch B in breast cancer (BC) and elucidate its molecular mechanisms, with a specific focus on the gut microbiota\u2013immune axis. Methods: In vitro, CCK-8, colony formation, and 3D spheroid assays were used to evaluate the effects of Sch B on proliferation inhibition and radiosensitization, flow cytometry and immunofluorescence were used to elucidate the mechanisms involved. In vivo, 4T1 tumor-bearing mice were treated with Sch B, and 16S rDNA sequencing and LC-MS\/MS were used to analyze the gut microbiota and short-chain fatty acid (SCFA) metabolism. IHC and qPCR detected antitumor immune responses. Results: Sch B inhibited the proliferation of BC cells in a time- and dose-dependent manner with negligible toxicity to the mammary epithelial cell line MCF-10A. Furthermore, Sch B enhanced the radiosensitivity (sensitization enhancement ratio: 1.20~1.77) of BC by inducing G1 phase cell cycle arrest and delaying radiation-induced DNA double-strand break repair. In vivo, Sch B suppressed BC growth in BALB\/c mice without causing obvious systemic toxicity. Sch B reversed tumor-induced gut microbiota dysbiosis (restoring species abundance and the Firmicutes\/Bacteroidetes ratio, enriching beneficial genera such as Lactobacillus and Butyrobacter) and normalized SCFA profiles (correlative evidence). Furthermore, Sch B modulated systemic immune responses by increasing the expression of Ifng, Cxcl10, Ddx58 and promoting CD3+ and CD8+ T-cell infiltration in tumors. Conclusions: Sch B exerts BC radiosensitization through dual mechanisms, direct regulation of the cell cycle and DNA repair, and indirect modulation of the gut microbiota-immune axis (correlative evidence), highlighting it as a safe and effective candidate for improving the efficacy of BC radiotherapy.<\/jats:p>","DOI":"10.3390\/ph19060883","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:08:02Z","timestamp":1780535282000},"page":"883","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Schisandrin B Exerts Radiosensitizing Effects on Breast Cancer via Dual Mechanisms of Cell Cycle\/DNA Repair and Gut Microbiota-Immune Axis Modulation"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1586-486X","authenticated-orcid":false,"given":"Yanhua","family":"Fang","sequence":"first","affiliation":[{"name":"Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"},{"name":"The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian 116001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxuan","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian 116001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Tong","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian 116001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian 116001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeshuo","family":"Feng","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian 116001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyu","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian 116001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian 116001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9699-3689","authenticated-orcid":false,"given":"Lingyun","family":"Jia","sequence":"additional","affiliation":[{"name":"Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1644-4496","authenticated-orcid":false,"given":"Shanshan","family":"Liang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian 116001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/978-981-10-6020-5_5","article-title":"Studies on DNA Damage Repair and Precision Radiotherapy for Breast Cancer","volume":"1026","author":"Jiang","year":"2017","journal-title":"Adv. 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