Abstract
Ferroptosis, a unique form of regulated necrotic cell death, is caused by excessive iron-dependent lipid peroxidation. However, the underlying mechanisms driving ferroptosis in human cancers remain elusive. In this study, we identified TRIM3, an E3 ubiquitin-protein ligase, as a key regulator of ferroptosis. TRIM3 is downregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), two major types of non-small cell lung cancer (NSCLC). Forced expression of TRIM3 promotes cell death by enhancing the cellular level of ROS and lipid peroxidation. Moreover, our in vivo study determined that TRIM3 overexpression diminishes the tumorigenicity of NSCLC cells, indicating that TRIM3 functions as a tumor suppressor in NSCLC. Mechanistically, TRIM3 directly interacts with SLC7A11/xCT through its NHL domain, leading to SCL7A11 K11-linked ubiquitination at K37, which promotes SLC7A11 proteasome-mediated degradation. Importantly, TRIM3 expression exhibits a negative correlation with SCL7A11 expression in clinical NSCLC samples, and low TRIM3 expression is associated with a worse prognosis. This study reveals that TRIM3 functions as a tumor suppressor that can impede the tumorigenesis of NSCLC by degrading SLC7A11, suggesting a novel therapeutic strategy against NSCLC.