Identification of SLC3A2 as a Potential Therapeutic Target of Ferroptosis in Bladder Cancer

Bladder cancer (BC) represents the most prevalent malignancy within the urinary system. Mounting evidence underscores the critical involvement of ferroptosis in cancer pathogenesis; Consequently, this study delves into its molecular underpinnings and therapeutic potential specifically in BC.

We analyzed gene expression profiles from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) repositories. Ferroptosis-related genes (FRGs) were selected from the FerrDb database. Utilizing systematic bioinformatics analyses, we identify differentially expressed and prognostic FRGs and construct an FRGs prognostic model. Combined with protein-protein interaction (PPI) analysis, solute carrier family 3 member 2 (SLC3A2) was selected for further study. Following targeted small interfering RNA (siRNA)-mediated knockdown of SLC3A2 in BC cell lines, we conducted comprehensive functional assays to evaluate its effect on malignant phenotypes, ferroptosis, and cisplatin sensitivity.

SLC3A2 expression was significantly elevated in BC cells ( p < 0.001). Its knockdown inhibited the proliferation, migration, and invasion abilities and promoted erastin-induced ferroptosis, as evidenced by increased reactive oxygen species (ROS), lipid peroxidation, and iron accumulation (all p < 0.05). SLC3A2 depletion also enhanced cisplatin sensitivity.

Collectively, these findings establish SLC3A2 as playing a vital oncogenic role in BC tumorigenesis and progression. Its function in inhibiting ferroptosis-especially during cisplatin-based chemotherapy-makes it a promising therapeutic target.