Mechanism of RSL3-induced ferroptotic cell death in HT22 cells: crucial role of protein disulfide isomerase

• RSL3 induces ferroptosis in HT22 cells via a novel pathway involving TrxR1 inhibition, PDI activation, NOS dimerization, and NO accumulation, in addition to GPX4 inhibition. • PDI acts as a crucial upstream mediator of RSL3-induced ferroptosis, linking oxidative stress to nitric oxide signaling. • Genetic or pharmacological inhibition of PDI or TrxR1 significantly abrogates RSL3-induced ferroptosis, suggesting potential therapeutic targets for ferroptosis-related diseases. • The study provides mechanistic insights into the crosstalk between thioredoxin and nitric oxide systems in ferroptotic cell death, with implications for cancer therapy and neurodegeneration.