TAZ/NRF2 positive feedback loop contributes to proliferation in bladder cancer through antagonistic ferroptosis

Abstract Bladder cancer (BLCA) is a prevalent malignancy characterized by high recurrence and metastasis rates. Emerging evidence suggests that the NRF2-GPX4 axis is closely associated with ferroptosis. The transcriptional coactivator with PDZ-binding motif (TAZ) plays a crucial role in regulating ferroptosis; however, its role in BLCA remains unclear. In our study, we found that TAZ was markedly upregulated in BLCA tissues and BLCA cell lines. Gene set enrichment analysis indicated that TAZ depletion was related to ferroptosis and glutathione metabolism. Our results demonstrated that TAZ promotes the malignant progression of BLCA cells both in vitro and in vivo. Moreover, TAZ enhances NRF2 transcriptional activity through interaction with NRF2. We further revealed that TAZ-TEAD4 regulates NRF2 expression at the transcriptional level. Additionally, NRF2 regulates TAZ transcription by binding to its promoter region, establishing a positive feedback loop between TAZ and NRF2 that sustains GPX4 activation and inhibits ferroptosis in BLCA. These insights provide novel molecular targets for therapeutic treatment in BLCA.