Ferroptosis as a therapeutic vulnerability in ARID1A-deficient bladder cancer

ARID1A is among the most frequently mutated genes in bladder cancer, yet no targeted therapy exists for this molecular subset. Here, we identify ferroptosis induction as a synthetic lethal strategy in ARID1A-deficient bladder cancer. We found that ARID1A loss impaired the NRF2-SLC7A11-glutathione (GSH) axis, leading to redox imbalance and profound sensitivity to the ferroptosis inducer RSL-3. In vitro, ARID1A knockdown depleted intracellular GSH and enhanced RSL-3-induced lipid peroxidation and cell death. Mechanistically, ARID1A directly regulated NRF2 transcription and its target SLC7A11, and restoring SLC7A11 or NRF2 activity or GSH levels rescued ferroptosis sensitivity. In vivo, RSL-3 treatment delayed tumor progression, reduced muscle invasion, and improved survival in two types of Arid1a -deficient mouse models. Furthermore, patient-derived organoids from ARID1A-low human tumors exhibited heightened RSL-3 sensitivity rather than ARID1A-high tumor. Our findings establish ferroptosis as a targetable vulnerability in ARID1A-deficient bladder cancer and provide a compelling rationale for clinical translation of ferroptosis-based therapies in this molecularly defined population. ARID1A-deficient bladder cancer exhibits heightened sensitivity to the ferroptosis inducer RSL-3 due to impaired NRF2-SLC7A11-GSH axis, establishing a targetable vulnerability and precision therapeutic strategy for this common mutant subtype.