Abstract

Cholesterol metabolic reprogramming is an emerging vulnerability in cancer, yet clinical progress has been limited by a lack of druggable targets. Here, we identify the sterol-sensing domain (SSD) of SCAP as a target in gastric cancer (GC), with multi-omics confirming tumor-specific SCAP overexpression, poor prognosis, and hyperactivated synthesis. Using SSD structure-based high-throughput screening, we discovered that the natural compound Platycodin D (PD) is a small-molecule inhibitor of SCAP. PD sustains SREBP2 activation yet paradoxically blocks cholesterol efflux. The underlying mechanism is that PD specifically disrupts SCAP's sterol-sensing function, thereby permitting unrestrained SREBP2-mediated 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-mediated efflux. We further demonstrate that this SCAP targeting initiates GPX4 cascade-mediated ferroptosis, which was reversible by inhibiting cholesterol synthesis or the stress response. PD 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.