%0 Journal Article
%T CST1 Suppresses Ferroptosis to Drive Gastric Cancer Metastasis via OTUB1-Mediated Stabilization of GPX4
%A Niels Henrik Rasmussen
%A Thomas Emil Sørensen
%J Archive of International Journal of Cancer and Allied Science
%@ 3108-4834
%D 2025
%V 5
%N 2
%R 10.51847/NEuzwcD1pJ
%P 51-77
%X Metastasis is a key contributor to poor survival in gastric cancer patients, yet the underlying molecular mechanisms remain largely unclear. In this study, we investigated the potential role of cystatin SN (CST1), a cysteine protease inhibitor, in facilitating gastric cancer metastasis. We proposed that CST1 might drive cancer progression by influencing GPX4 and regulating ferroptosis. Transcriptome-wide analysis revealed that CST1 levels were markedly higher in metastatic tumors, and patients with elevated CST1 had poorer clinical outcomes. Functional experiments demonstrated that CST1 overexpression significantly enhanced the migratory and invasive abilities of gastric cancer cells in vitro and promoted metastasis to the liver, lungs, and peritoneum in mouse models. Additionally, high CST1 expression was associated with activation of the epithelial-mesenchymal transition (EMT) program. Mechanistically, CST1 was found to interact directly with GPX4, a central regulator of ferroptosis, as shown by co-immunoprecipitation and mass spectrometry. CST1 increased GPX4 protein stability by recruiting OTUB1, which reduced GPX4 ubiquitination, leading to decreased intracellular reactive oxygen species (ROS) levels and inhibition of ferroptosis. Through this mechanism, CST1 contributes to enhanced metastatic potential in gastric cancer cells. Clinically, CST1 levels were elevated in the peripheral blood and ascites of patients with metastatic disease, and multivariate Cox regression identified CST1 as an independent prognostic marker. In summary, our study uncovers a pathway whereby CST1 protects gastric cancer cells from ferroptotic cell death, thereby promoting tumor progression and metastasis. These findings highlight CST1 as a promising biomarker and therapeutic target for managing metastatic gastric cancer.
%U https://smerpub.com/article/cst1-suppresses-ferroptosis-to-drive-gastric-cancer-metastasis-via-otub1-mediated-stabilization-of-g-iub5fmvlsx3ngav