Abstract

Lung adenocarcinoma is the most common subtype of lung cancer and the leading cause of cancer‐related mortality worldwide. Ferroptosis, a regulated form of cell death characterized by iron‐dependent lipid peroxidation, has emerged as a promising therapeutic target for lung adenocarcinoma. However, the molecular mechanisms that control ferroptosis sensitivity remain unclear. In this study, we identified ubiquitin‐specific protease 45 (USP45) as a critical suppressor of ferroptosis in lung adenocarcinoma cells. Systematic screening of ubiquitin‐specific proteases revealed that USP45 robustly enhanced glutathione peroxidase 4 (GPX4) protein expression. Bioinformatics analysis indicates that USP45 is significantly upregulated in lung adenocarcinoma patient datasets from the GEO and TCGA databases. Immunohistochemical results from the HPA database further corroborate this finding. Concurrently, elevated USP45 expression in lung adenocarcinoma patients frequently portends an unfavorable prognosis. Functional assays showed that USP45 depletion sensitized lung adenocarcinoma cells to erastin‐induced ferroptosis, leading to impaired viability, colony formation, survival, migration, and invasion, whereas USP45 overexpression conferred resistance to ferroptotic stress and rescued the malignant phenotypes. Mechanistically, USP45 interacts with GPX4 and removes its ubiquitin chains, thereby stabilizing the GPX4 protein. Overexpression of GPX4 rescued ferroptosis sensitivity in USP45‐deficient lung adenocarcinoma cells, whereas GPX4 depletion abrogated the protective effect of USP45 overexpression, establishing GPX4 as a functional mediator of USP45 activity. Collectively, these findings reveal a previously unknown USP45–GPX4 axis that promotes ferroptosis resistance and tumor progression in lung adenocarcinoma.