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In this study, TSN inhibited melanoma cell proliferation and cell\u2010cycle progression, induced apoptosis, and suppressed metastasis in both in vitro and in vivo models. TSN is a potent PI3K inhibitor; here, we identify basonuclin 2 (BNC2) as a transcription factor critically involved in TSN's suppression of\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    transcription in melanoma cells. In clinical samples and melanoma datasets, BNC2 expression is substantially elevated in skin cutaneous melanoma and correlates with poor patient metastasis. Functional studies demonstrate that BNC2 promotes melanoma cell proliferation and migration. TSN directly binds to BNC2 and CRBN, the substrate receptor subunit of the E3 ubiquitin ligase complex, acting as a molecular glue to induce ubiquitin\u2010dependent degradation of BNC2 and subsequent downregulation of\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    transcription. TSN nanoliposome encapsulation improves cellular uptake, tumor targeting, and anti\u2010metastatic efficacy of TSN in vivo. These findings reveal a context\u2010dependent oncogenic function of BNC2 in melanoma, contrasting with its previously described tumor\u2010suppressive roles in other cancers, and establish TSN as a small\u2010molecule degrader of BNC2 with therapeutic potential for melanoma.\n                  <\/jats:p>","DOI":"10.1002\/advs.77458","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:07:49Z","timestamp":1788142069000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural Product Toosendanin Suppresses the Malignant Development of Skin Melanoma by Targeting BNC2 for Degradation"],"prefix":"10.1002","author":[{"given":"Hui","family":"Dai","sequence":"first","affiliation":[{"name":"State Key lab of Pharmaceutical Biotechnology (SKLPB) College of Life Sciences in Nanjing University (Xianlin Campus) Nanjing University  Nanjing 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