Eupalinolide B exerts cytotoxic effects against KRAS‑mutant NSCLC through Nrf2/HO‑1‑regulated ferroptosisOA

Ferroptosis,an iron‑dependent form of regulated cell death,is characterized by excessive reactive oxygen species(ROS)accumulation and lipid peroxidation of polyunsaturated fatty acids(PUFAs)in cellular membranes.Non‑small cell lung cancer(NSCLC)harboring KRAS mutations often exhibits therapeutic resistance but may display high susceptibility to ferroptosis.Eupalinolide B(EB),a natural compound with documented anti‑cancer activity,has not been thoroughly explored for its ferroptosis‑inducing potential in KRAS‑mutant NSCLC.In this study,we demonstrate that EB treatment significantly elevates ROS levels,intracellular iron accumulation,and lipid peroxidation in KRAS‑mutant NSCLC cells,resulting in ferroptotic cell death.Molecular docking and cellular thermal shift assays reveal that EB directly binds to and activates heme oxygenase‑1(HO‑1),a critical component of the Kelch‑like ECH‑associated protein 1(Keap1)‑Nrf2/HO‑1 oxidative stress response pathway.Genetic or pharmacological inhibition of HO‑1 attenuates EB‑induced ferroptosis,underscoring the pivotal role of HO‑1‑mediated oxidative stress in this process.Furthermore,in vivo studies using KRAS‑mutant H358 xenograft models confirm the potent anti‑tumor effects of EB.Collectively,our findings establish that EB triggers ferroptosis in KRAS‑mutant NSCLC by activating the Keap1‑Nrf2/HO‑1 pathway,suggesting a promising therapeutic strategy for this challenging malignancy.