Cisplatin remains a fundamental component in the treatment of bladder cancer despite recent advances in immunotherapy. However, resistance to cisplatin significantly limits its long-term efficacy. Ferroptosis, a form of regulated cell death driven by iron accumulation and lipid peroxidation, has been increasingly recognized as a pivotal mechanism underlying the cytotoxicity of cisplatin. Yet, how bladder cancer cells evade ferroptosis during the development of drug resistance is still not fully understood.

We generated a cisplatin-resistant bladder cancer cell line (T24R) and systematically profiled its ferroptosis-associated characteristics using a combination of biochemical assays, advanced imaging techniques, and flow cytometry. Specific markers involved in redox homeostasis, iron metabolism, and lipid peroxidation were analyzed to delineate the resistant phenotype.

T24R cells demonstrated a ferroptosis-resistant profile, including diminished reactive oxygen species (ROS) and lipid peroxidation, lower intracellular ferrous iron levels, and elevated expression of ferroptosis-inhibitory factors such as solute carrier family 7 member 11 (SLC7A11) and glutathione hydroperoxidase 4 (GPX4). Additionally, an increase in lipid droplet formation was observed, indicating potential lipid remodeling that may support survival under oxidative stress.

These findings reveal that suppression of ferroptosis is closely associated with acquired cisplatin resistance in bladder cancer. Targeting ferroptosis-related vulnerabilities may offer a promising therapeutic avenue to restore chemosensitivity and improve treatment outcomes.