CST1 stabilizes GPX4 to suppress ferroptosis and promote bladder cancer progression

Abstract

Cystatin SN (CST1), a cysteine protease inhibitor, participates in various cancers, yet its function and mechanism in bladder cancer (BCa) are unclear. Public databases, BCa cells and clinical samples were used to analyze CST1 expression profiles. Functional experiments detected cell proliferation, migration and invasion. Intracellular iron, ROS, MDA, GSH and mitochondrial morphology reflected ferroptosis. Co-IP assays verified the intracellular interaction between CST1 and GPX4, and ubiquitination assays clarified GPX4 stabilization via suppressed proteasomal degradation. Xenograft and rescue assays validated the CST1-GPX4 axis. The expression of CST1 is markedly higher in bladder cancer cells than in normal urothelial cells. CST1 knockdown inhibits malignant phenotypes and induces ferroptosis. CST1 binds GPX4 to block its ubiquitination and post-translationally elevate GPX4 protein without altering its transcription. GPX4 overexpression rescues CST1 silencing-induced ferroptosis and growth defects. In vivo CST1 facilitates tumor growth and GPX4 upregulation. CST1 interacts with GPX4 to inhibit its ubiquitin-dependent degradation, suppress ferroptosis and promote BCa progression, and may serve as a potential therapeutic target for bladder cancer.