JS-K induces autophagy-dependent ferroptosis in bladder cancer: a multimodal mechanistic and translational study.

Background: Bladder cancer is the most common urological malignancy. Bladder cancer has limited therapeutic options, especially in advanced stages. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising target for cancer therapy. However, the role of autophagy in modulating ferroptosis remains incompletely understood. Methods: We investigated the anti-tumor effects of JS-K, a nitric oxide-releasing prodrug, in bladder cancer through integrated cell, animal, and patient data studies. Results: JS-K induced mitochondrial damage, lipid peroxidation, reactive oxygen species accumulation, and intracellular iron overload in bladder cancer cells in a concentration-dependent manner. These changes were accompanied by downregulation of GPX4 and SLC7A11 and upregulation of FTH1 and TFR1, indicative of ferroptosis. Inhibition or knockdown of the autophagy marker Conclusions: JS-K induces autophagy-dependent ferroptosis in bladder cancer cells and significantly suppresses tumor progression. Targeting the autophagy-ferroptosis axis offers a novel therapeutic strategy for bladder cancer treatment.