XBP1s/SCD1介导的脂代谢对铁死亡在NSCLC顺铂耐药中的影响及机制研究

非小细胞肺癌是肿瘤中的“第一杀手”，含铂类药物的化疗是主要治疗手段，但耐药发生率高，是目前最亟需解决的问题。铁死亡抵抗是顺铂耐药的重要机制。MUFAs可调控脂质过氧化，影响铁死亡；XBP1s和SCD1均可调控油酸代谢。本团队前期研究发现对铂类化疗不敏感的NSCLC患者癌组织中油酸表达含量高，XBP1s亦高表达，且与预后相关；顺铂耐药细胞铁死亡作用被抑制；激活铁死亡通路，能逆转细胞的耐药状态；XBP1s在耐药细胞中高表达，转录调控SCD1。据此我们提出假说：在顺铂耐药细胞中，XBP1s通过转录调控SCD1的表达，促进油酸的生成，抑制铁死亡的发生；抑制XBP1s表达可促进顺铂耐药细胞发生铁死亡，从而逆转耐药。本项目利用脂质组学、基因编辑、RNA-seq和ChIP-seq等方法，研究XBP1s/SCD1介导的脂代谢通路影响NSCLC耐药后顺铂引起的铁死亡作用，为含铂类化疗耐药的防治提供新思路。

Non-small cell lung cancer (NSCLC) is the "first killer" of tumors, and chemotherapy containing platinum-based drugs is the main treatment method. However, the high incidence of drug resistance is the most urgent problem to be solved at presen. Ferroptosis resistance is an important mechanism of cisplatin resistance. MUFAs can regulate lipid peroxidation and affect ferroptosis. Both XBP1S and SCD1 can regulate oleic acid metabolism. Our previous study found that the expression of oleic acid and XBP1s were high in cancer tissues of NSCLC patients who were insensitive to platinum-based chemotherapy, and they were correlated with prognosis. Ferroptosis was inhibited in cisplatin resistant cells. Activating ferroptosis pathway can reverse the drug resistance of cells. XBP1s is highly expressed in drug-resistant cells and transcriptionally regulates SCD1. Based on this, we hypothesized that XBP1s regulates SCD1 expression through transcriptional regulation in cisplatin resistant cells, promoting oleic acid production and inhibiting ferroptosis. Inhibition of XBP1s can promote ferroptosis in cisplatin-resistant cells, thus reversing cisplatin resistance. In this project, lipidomics, gene editing, RNA-seq and ChIP-seq methods were used to study the effect of XBP1s/ SCD1-mediated lipid mcetabolism pathway on ferroptosis induced by cisplatin after NSCLC drug resistance, providing a new idea for the prevention and treatment of platinum-containing chemotherapy drug resistance.