The study investigates the role of SPTBN2 in ferroptosis and its potential as a therapeutic target in non-small cell lung cancer (NSCLC). SPTBN2, a membrane-cytoskeleton protein, was found to suppress ferroptosis by facilitating the membrane localization and function of SLC7A11, a key subunit of System Xc−, which mediates cystine uptake and glutathione (GSH) synthesis. SPTBN2 interacts with SLC7A11 through its CH domain and connects it with the motor protein Arp1, enhancing the transport of SLC7A11 from the cytoplasm to the membrane. This interaction is crucial for maintaining the activity of System Xc− and preventing ferroptosis. Inhibition of SPTBN2 increased the sensitivity of NSCLC cells to cisplatin-induced ferroptosis both in vitro and in vivo. Additionally, Abrine, a potential SPTBN2 inhibitor, was identified and validated for its ability to promote ferroptosis and sensitize NSCLC cells to cisplatin. The study concludes that SPTBN2 is a potential therapeutic target for addressing ferroptosis dysfunction and cisplatin resistance in NSCLC.The study investigates the role of SPTBN2 in ferroptosis and its potential as a therapeutic target in non-small cell lung cancer (NSCLC). SPTBN2, a membrane-cytoskeleton protein, was found to suppress ferroptosis by facilitating the membrane localization and function of SLC7A11, a key subunit of System Xc−, which mediates cystine uptake and glutathione (GSH) synthesis. SPTBN2 interacts with SLC7A11 through its CH domain and connects it with the motor protein Arp1, enhancing the transport of SLC7A11 from the cytoplasm to the membrane. This interaction is crucial for maintaining the activity of System Xc− and preventing ferroptosis. Inhibition of SPTBN2 increased the sensitivity of NSCLC cells to cisplatin-induced ferroptosis both in vitro and in vivo. Additionally, Abrine, a potential SPTBN2 inhibitor, was identified and validated for its ability to promote ferroptosis and sensitize NSCLC cells to cisplatin. The study concludes that SPTBN2 is a potential therapeutic target for addressing ferroptosis dysfunction and cisplatin resistance in NSCLC.