GPX4-dependent Glutathione (GSH) high consumption drives platinum chemotherapeutic resistance by inhibiting ferroptosis in lung cancer derived brain metastasis

Platinum-based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows limited therapeutic efficacy in patients with brain metastasis (BM). In this study, we utilized a BM model of PC9 lung adenocarcinoma cells and found that the derivative brain metastatic subpopulations (PC9-BrMs) of parental cells PC9 developed obvious resistance to platinum; this suggested that the acquisition of chemo-resistance by brain metastatic cells is attributable to the intrinsic changes in the metastatic cells. Therefore, we performed an integrated profiling of metabolomics and proteomics, and described a radically altered spectrum of BM metabolism and protein expression compared with primary lung cancer cells. We identified a unique metabolite status characterized by high consumption of glutathione (GSH) for antioxidant stress response, both in BM cells and clinical serum samples.