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journal article·2026-06-29Open access

Functional Suppression of SCAP Triggers Endoplasmic Reticulum Stress‐Dependent Ferroptosis by Impairing Cholesterol Metabolism in Gastric Cancer

Qianqian Xu, Guangzhao Pan, Lele Zhang, Xiangliu Chen, Kui Zhang, Yang Lu, Zibo Duan, Aiping Chen, Hailong Shen, Yuxi Zhang, Xiaowu Dong, Jinzhou Huang, Xing Huang, Kai Miao, Qian Hua, Fangfang Tao, Weidong Zhang, Jiang‐Jiang Qin

Advanced Science
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Abstract

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.
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Research context

OpenAlex topics: Ferroptosis and cancer prognosis · Cancer, Lipids, and Metabolism · Cholesterol and Lipid Metabolism

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Center for Innovative Drug Research Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang China

Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang China

School of Basic Medical Sciences Zhejiang Chinese Medical University Hangzhou Zhejiang China

School of Preclinical Medicine Chengdu University Chengdu China

Pritzker School of Molecular Engineering Ben May Department for Cancer Research University of Chicago Chicago USA

Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences Zhejiang University Hangzhou Zhejiang China

School of Life Sciences Beijing University of Chinese medicine Beijing China

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang China

MOE Frontier Science Centre for Precision Oncology University of Macau Macau SAR China

Zhejiang Key Laboratory of Blood‐Stasis‐Toxin Syndrome, Zhejiang Chinese Medical University China Collaborative Graduate School of Traditional Chinese Medicine Hangzhou Zhejiang China

Institute of Medicinal Plant Development Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

Department of Phytochemistry School of Pharmacy Second Military Medical University Shanghai China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Zhejiang Province

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