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Icaritin (ICT), a bioactive flavonoid, demonstrates significant anti-tumor activity but lacks defined molecular targets. This study employs an advanced strategy integrating proteolysis targeting chimera (PROTAC) technology with quantitative proteomics to identify ICT\u2019s key targets. A library of 22 ICT-based PROTAC derivatives were synthesized, among which LJ-41 exhibited a superior IC50 of 5.52 \u03bcM against Burkitt lymphoma (CA-46) cells. Then, differential proteomic analysis identified Bax inhibitor-1 (BI-1) as a potential target. Target validation techniques, including cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) assay, surface plasmon resonance (SPR) assay, and molecular docking, confirmed LJ-41\u2019s high specificity for BI-1. Mechanistic investigations revealed that LJ-41 induces apoptosis through BI-1 degradation, triggering endoplasmic reticulum stress and activating inositol-requiring enzyme 1 \u03b1 (IRE1\u03b1), activating transcription factor 6 (ATF6), and nuclear factor erythroid 2-related factor transcription factor heme oxygenase 1 (NRF2-HO-1) signaling pathways. This study establishes a refined methodological framework for natural product target discovery and highlights ICT-PROTAC derivatives\u2019 potential for clinical application in Burkitt lymphoma treatment.<\/jats:p>","DOI":"10.3390\/ijms252312944","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T06:58:58Z","timestamp":1733122738000},"page":"12944","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Advanced PROTAC and Quantitative Proteomics Strategy Reveals Bax Inhibitor-1 as a Critical Target of Icaritin in Burkitt Lymphoma"],"prefix":"10.3390","volume":"25","author":[{"given":"Peixi","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiming","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Shi","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaolai","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenlei","family":"Lian","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5844-9984","authenticated-orcid":false,"given":"Junjie","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieqing","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medicine, Huaqiao University, Quanzhou 362021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/j.apsb.2021.08.020","article-title":"Emerging role of natural products in cancer immunotherapy","volume":"12","author":"Dong","year":"2022","journal-title":"Acta Pharm. 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