Ciprofloxacin Enhances RSL3-Induced Ferroptosis by Promoting Mitochondrial Zn2+ Accumulation via the STING1-CAV2 Pathway

Ciprofloxacin (CFX) is a broad-spectrum antibiotic belonging to the fluoroquinolone class, widely used to treat bacterial infections by inhibiting bacterial DNA replication. Ferroptosis, a form of regulated cell death, is characterized by lipid peroxidation on cellular and organelle membranes. Our previous studies demonstrated that ciprofloxacin inhibits erastin-induced ferroptosis by enhancing glutathione peroxidase 4 (GPX4) protein stability. In contrast, we report here a distinct role of ciprofloxacin in potentiating RSL3-induced ferroptosis in various cancer cells. Mechanistically, CFX inhibits topoisomerase 2β (TOP2B), and when combined with RSL3, induces significant mitochondrial DNA (mtDNA) stress. This mtDNA stress triggers a signaling cascade involving the stimulator of interferon genes cGAMP interactor 1 (STING1) and caveolin-2 (CAV2), ultimately disrupting intracellular zinc homeostasis. The resulting zinc accumulation is transported into mitochondria via solute carrier family 25 member 25 (SLC25A25), leading to elevated mitochondrial reactive oxygen species (ROS) production and amplification of ferroptosis. These findings reveal a dual role of ciprofloxacin in ferroptosis regulation, dependent on the specific stimuli and downstream signaling pathways activated. This dual functionality highlights the potential therapeutic implications of ciprofloxacin in modulating ferroptosis in disease contexts.