GLI2 confers ferroptosis resistance in bladder cancer by transcriptionally upregulating PRDX1.

Bladder cancer represents a significant disease burden in men, as it is both highly common and a leading cause of cancer-related deaths. Despite advances in personalized therapies, patient outcomes continue to show considerable variability, and there is an urgent need to explore novel therapeutic targets for this disease. Ferroptosis has recently been implicated in chemotherapy response and proposed as a therapeutic target in various cancers; however, its regulatory mechanism in bladder cancer cells has not been fully elucidated. In this study, we analyzed public data from the GEO database and found that the transcription factor GLI2 was significantly upregulated in bladder cancer compared with normal bladder tissues. Functional assays revealed that GLI2 promotes malignant progression and represses ferroptosis in bladder cancer cells. Mechanistically, RNA sequencing and chromatin immunoprecipitation (ChIP) assays showed that GLI2 transcriptionally regulates the expression of peroxiredoxin 1 (PRDX1), a well-characterized ferroptosis-inhibiting gene. Additionally, rescue assay results indicated that PRDX1 mediates the role of GLI2 in ferroptosis repression and promotes malignant progression of bladder cancer. More importantly, inhibition of GLI2 via siRNA or a small-molecule inhibitor sensitized bladder cancer cells to both PRDX1 inhibitors and cisplatin. Together, these findings delineate a regulatory axis involving GLI2-PRDX1-mediated ferroptosis, provide mechanistic insights into its critical role in driving bladder cancer progression and chemosensitivity, and offer potential therapeutic targets for future clinical intervention.