Characterization of the mechanisms underlying sulfasalazine-induced ferroptotic cell death: role of protein disulfide isomerase-mediated NOS activation and NO accumulation

• Sulfasalazine induces ferroptosis in H9C2 cardiomyocytes and BRL-3A hepatocytes via a sequential buildup of NO, ROS, and lipid-ROS. • PDI mediates SAS-induced iNOS dimerization and NO accumulation, which are upstream of oxidative damage. • Inhibition of PDI activity or knockdown of PDI suppresses SAS-induced ferroptosis, while PDI activation sensitizes cells. • The PDI-NOS-NO axis is a critical pathway for SAS cytotoxicity, offering potential therapeutic targets for modulating ferroptosis.