Microsomal glutathione transferase 1 confers cisplatin resistance of non-small cell lung cancer via interaction with arachidonate lipoxygenase 5 to repress ferroptosis.

Cisplatin (DDP) resistance remains a primary cause of chemotherapy failure and recurrence of non-small cell lung cancer (NSCLC). Abnormal high microsomal glutathione transferase 1 (MGST1) expression has been found in DDP-resistant NSCLC cells. This study aimed to explore the function and mechanism of MGST1 in DDP resistance of NSCLC cells. The expression levels of target molecules were assessed by quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting. Cell proliferation was evaluated by cell counting kit-8 (CCK-8) and colony formation assays. Ferroptosis was determined by malondialdehyde (MDA), glutathione (GSH), Fe2+, and reactive oxygen species (ROS) levels. The interaction between proteins was confirmed by Co-immunoprecipitation (Co-IP). The effect of MGST1 on DDP resistance was evaluated using the tumor xenograft assay in vivo. Immunohistochemical staining was performed to measure Ki-67 and p-H2A.X expression in tumor tissues. MGST1 expression was higher, while arachidonate lipoxygenase 5 (ALOX5) expression was lower in DDP-resistant NSCLC patients and cells. MGST1 ablation sensitized NSCLC cells to DDP therapy through inducing ferroptosis. MGST1 protein directly interacted with ALOX5 protein to restrain ALOX5-triggered ferroptosis. Ferroptosis inhibitor or sh-ALOX5 reversed the promotive effect of MGST1 silencing on the DDP sensitivity of NSCLC cells. Finally, MGST1 depletion sensitized NSCLC cells to DDP therapy in nude mice in vivo. MGST1 high expression contributed to DDP resistance of NSCLC cells by inhibiting ALOX5-induced ferroptosis. Our results provide a potential therapeutic target for overcoming DDP resistance in NSCLC patients.