• Eupalinolide B (EB) induces ferroptosis in KRAS-mutant NSCLC cells by elevating ROS, iron accumulation, and lipid peroxidation.
• EB directly binds to and activates HO-1, a key component of the Keap1-Nrf2/HO-1 pathway, driving oxidative stress and ferroptosis.
• Inhibition of HO-1 (genetic or pharmacological) attenuates EB-induced ferroptosis, confirming its mechanistic role.
• In vivo xenograft studies demonstrate EB's potent anti-tumor efficacy, positioning it as a promising therapeutic for KRAS-mutant NSCLC.