SPTBN2 suppresses ferroptosis in NSCLC cells by facilitating SLC7A11 membrane trafficking and localization. SPTBN2, a membrane-cytoskeleton protein, interacts with SLC7A11 through its CH domain and connects it with Arp1, a key component of the dynactin complex, thereby facilitating SLC7A11 membrane localization. This process is essential for SLC7A11's role in System Xc⁻, which mediates cystine uptake and GSH synthesis, crucial for preventing ferroptosis. SPTBN2 suppression enhances NSCLC cell resistance to ferroptosis inducers, while its inhibition increases sensitivity to cisplatin by inducing ferroptosis. Abrine, a potential SPTBN2 inhibitor, promotes ferroptosis and sensitizes NSCLC cells to cisplatin both in vitro and in vivo. SPTBN2 inhibition enhances ferroptosis-based cisplatin therapy in vivo, as demonstrated by reduced tumor volume and increased lipid peroxidation markers. These findings suggest that SPTBN2 is a potential therapeutic target for addressing ferroptosis dysfunction and cisplatin resistance in NSCLC. The study provides new molecular targets and therapeutic strategies for NSCLC treatment.SPTBN2 suppresses ferroptosis in NSCLC cells by facilitating SLC7A11 membrane trafficking and localization. SPTBN2, a membrane-cytoskeleton protein, interacts with SLC7A11 through its CH domain and connects it with Arp1, a key component of the dynactin complex, thereby facilitating SLC7A11 membrane localization. This process is essential for SLC7A11's role in System Xc⁻, which mediates cystine uptake and GSH synthesis, crucial for preventing ferroptosis. SPTBN2 suppression enhances NSCLC cell resistance to ferroptosis inducers, while its inhibition increases sensitivity to cisplatin by inducing ferroptosis. Abrine, a potential SPTBN2 inhibitor, promotes ferroptosis and sensitizes NSCLC cells to cisplatin both in vitro and in vivo. SPTBN2 inhibition enhances ferroptosis-based cisplatin therapy in vivo, as demonstrated by reduced tumor volume and increased lipid peroxidation markers. These findings suggest that SPTBN2 is a potential therapeutic target for addressing ferroptosis dysfunction and cisplatin resistance in NSCLC. The study provides new molecular targets and therapeutic strategies for NSCLC treatment.