ELK1-YBX1 signaling promotes cisplatin resistance via ferroptosis adaptation in bladder cancer.

Bladder cancer (BC) is one of the most common malignancies of the urinary system, and chemoresistance remains a major obstacle limiting the clinical efficacy of cisplatin-based chemotherapy. Elucidating the mechanisms underlying cisplatin resistance may facilitate the identification of potential therapeutic targets and ultimately improve patient outcomes. In this study, we found that Y-box binding protein 1 (YBX1) was upregulated in bladder cancer tissues with poor chemotherapeutic response as well as in cisplatin-resistant bladder cancer cell lines, where it promoted tumor cell proliferation and invasion. Functional assays demonstrated that depletion of YBX1 significantly enhanced cisplatin sensitivity in both in vitro and in vivo. Mechanistically, elevated YBX1 expression was associated with reduced ferroptosis sensitivity in cisplatin-resistant cells. Although YBX1 induced autophagy and was accompanied by a reduction in glutathione peroxidase 4 (GPX4) protein levels, the overall enhancement of intracellular antioxidant capacity in resistant cells may partially offset the increased susceptibility to ferroptosis caused by GPX4 degradation. Furthermore, we identified the transcription factor ELK1 as an upstream regulator that transcriptionally upregulates YBX1, while YBX1 may contribute to the cisplatin-resistant phenotype through activation of the p62-NRF2-associated antioxidant pathway. Collectively, these findings highlight a critical role of YBX1 in cisplatin resistance and suggest that targeting YBX1 may represent a promising strategy for overcoming cisplatin-based chemoresistance in bladder cancer.