#1393

Suppression of ferroptosis through the SLC7A11/GPX4 axis drives chemotherapy resistance of bladder cancer

K. Chen¹, E. Chen², G. Liu³, C. Chen⁴, C. Peng⁴

¹Taipei Medical University Shuang-Ho Hospital, Department of Urology, New Taipei City, Taiwan
²Medical College of Wisconsin, Medical School, Milwaukee, WI, United States
³Methodist Health Care, Graduate Medical Education, San Antonio, TX, United States
⁴Taipei Medical University, Graduate Institute of Clinical Medicine, College of Medicine, Taipei, Taiwan

Introduction:

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.

Material and methods:

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.

Results:

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.