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This study aimed to evaluate the antitumor effects and underlying mechanisms of Z\u2010guggulsterone (Z\u2010GS), a natural product, in TNBC. Human TNBC cell lines (MDA\u2010MB\u2010231 and MDA\u2010MB\u2010468) were treated with Z\u2010GS to assess proliferation, cell\u2010cycle progression, apoptosis, and reactive oxygen species (ROS) accumulation. Autophagic flux and the OGT\u2013SNAP29 signaling axis were investigated via Western blotting, immunofluorescence, molecular docking, and molecular dynamics simulation. In\u00a0vivo, the antitumor efficacy and safety were evaluated using TNBC xenografts in zebrafish and BALB\/c nude mice. Z\u2010GS selectively suppressed TNBC cell proliferation, induced cell\u2010cycle arrest and apoptosis, and increased intracellular ROS. Mechanistically, Z\u2010GS upregulated O\u2010GlcNAc transferase (OGT) expression, enhanced SNAP29 O\u2010GlcNAcylation, disrupted SNARE complex assembly, inhibited autophagosome\u2013lysosome fusion, and blocked late\u2010stage autophagic flux. In\u00a0vivo, Z\u2010GS significantly inhibited TNBC xenograft growth without detectable toxicity. Z\u2010GS functions as a novel late\u2010stage autophagy inhibitor and exhibits selective anti\u2010TNBC activity, bridging natural product pharmacology and cancer treatment.<\/jats:p>","DOI":"10.1002\/ptr.70272","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T08:31:31Z","timestamp":1770971491000},"page":"2364-2379","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Z\u2010Guggulsterone Inhibits Triple\u2010Negative Breast Cancer Progression by Blocking Autophagosome\u2013Lysosome Fusion via\n                    <scp>OGT<\/scp>\n                    \u2010Mediated\n                    <scp>SNAP29<\/scp>\n                    O\u2010\n                    <scp>GlcNAcylation<\/scp>"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6062-8161","authenticated-orcid":false,"given":"Da","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Breast Surgery, General Surgery, Cancer Center Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College  Zhejiang Hangzhou China"},{"name":"Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer  Zhejiang Hangzhou China"},{"name":"Central Laboratory Changshu Hospital Affiliated to Soochow University  Changshu Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiao","family":"Mu","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, General Surgery, Cancer Center Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College  Zhejiang Hangzhou China"},{"name":"Key Laboratory for Diagnosis and 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