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Here, we identify the sterol\u2010sensing domain (SSD) of SCAP as a target in gastric cancer (GC), with multi\u2010omics confirming tumor\u2010specific SCAP overexpression, poor prognosis, and hyperactivated synthesis. Using SSD structure\u2010based high\u2010throughput screening, we discovered that the natural compound Platycodin D (PD) is a small\u2010molecule inhibitor of SCAP. PD sustains SREBP2 activation yet paradoxically blocks cholesterol efflux. The underlying mechanism is that PD specifically disrupts SCAP's sterol\u2010sensing function, thereby permitting unrestrained SREBP2\u2010mediated biosynthesis. This critical dysfunction leads to pathological cholesterol overload in the endoplasmic reticulum (ER), inducing proteotoxic stress. Consequently, this stress disrupts Nrf1 ER retention and forces nuclear translocation, thereby compromising LXR\u2010mediated efflux. We further demonstrate that this SCAP targeting initiates GPX4 cascade\u2010mediated ferroptosis, which was reversible by inhibiting cholesterol synthesis or the stress response.\u00a0PD demonstrated potent tumor suppression with a significantly improved safety profile compared to cisplatin in vivo. Our work establishes a causal link between SSD disruption and ferroptotic death via cholesterol dysregulation, introducing a novel paradigm for exploiting metabolic vulnerabilities in GC therapy.<\/jats:p>","DOI":"10.1002\/advs.76290","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T16:52:15Z","timestamp":1782751935000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Suppression of SCAP Triggers Endoplasmic Reticulum Stress\u2010Dependent Ferroptosis by Impairing Cholesterol Metabolism in Gastric Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Qianqian","family":"Xu","sequence":"first","affiliation":[{"name":"Center for Innovative Drug Research Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences  Hangzhou Zhejiang China"},{"name":"Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences  Hangzhou Zhejiang 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