目的 阐明薏苡仁脂亚微乳（Coicis Semen lipid submicron emulsion，CSE）调控代谢重编程诱导胰腺癌细胞铁死亡的作用机制。方法 构建高脂饮食原位胰腺癌荷瘤小鼠模型，探讨CSE抗肿瘤作用；利用UPLC-MS/MS技术检测胰腺肿瘤细胞内小分子代谢物和相关差异代谢途径；采用试剂盒检测CSE对脂肪细胞与胰腺癌细胞共培养模型中胰腺癌细胞内谷胱甘肽（glutathione，GSH）、谷胱甘肽过氧化物酶4（glutathione peroxidase 4，GPX4）、脂质蓄积、过氧化水平、活性氧（reactive oxygen species，ROS）、游离脂肪酸（free fatty acid，FFA）、亚铁离子、线粒体形态、线粒体膜电位（mitochondrial membrane potential，MMP）的影响；免疫组化染色、组织染色检测胰腺肿瘤组织内GPX4和溶质载体家族7成员11（recombinant solute carrier family 7，SLC7A11）的表达、脂质蓄积及脂质过氧化水平。结果CSE能够显著抑制胰腺肿瘤的生长（P＜0.001）；影响胰腺癌细胞内谷胱甘肽代谢和甘油磷脂代谢通路（P＜0.01）；增加脂肪细胞与胰腺癌细胞共培养模型中胰腺癌细胞内脂质积累、ROS和FFA水平、脂质过氧化和亚铁离子含量（P＜0.05），降低GSH、GPX4水平和MMP（P＜0.05）。铁死亡抑制剂（ferrostatin-1，Fer-1）与CSE联用能逆转CSE介导的胰腺癌细胞铁死亡（P＜0.05、0.01）。结论CSE可通过诱导细胞GSH耗竭和过氧化脂质蓄积，破坏细胞内氧化还原平衡，诱导铁死亡从而抑制胰腺癌细胞生长。

Objective To elucidate the role of Yiyiren (Coicis Semen) lipid submicron emulsion (CSE) in regulating metabolic reprogramming to induce ferroptosis in pancreatic cancer cells. Methods To investigate the anti-tumor effect of CSE by constructing a high-fat diet in situ pancreatic cancer-bearing mouse model; UPLC-MS/MS technology was used to detect small molecule metabolites and related differential metabolic pathways in pancreatic tumor cells. The kit was used to detect the effects of CSE on glutathione (GSH), glutathione peroxidase 4 (GPX4), lipid accumulation, peroxidation level, reactive oxygen species (ROS), free fatty acid (FFA), ferrous ion, mitochondrial morphology and mitochondrial membrane potential (MMP) in pancreatic cancer cells in the co-culture model of adipocytes and pancreatic cancer. The expression of GPX4 and recombinant solute carrier family 7 (SLC7A11), lipid accumulation and lipid peroxidation in pancreatic tumor tissues were detected by immunohistochemical staining and tissue staining. Results CSE significantly inhibited the growth of pancreatic tumors (P < 0.001). CSE significantly affected glutathione metabolism and glycerophospholipid metabolism pathways in pancreatic cancer cells (P < 0.01). CSE treatment significantly increased lipid accumulation, ROS, FFA, lipid peroxidation and ferrous ion content in pancreatic cancer cells in the co-culture model of adipocytes and pancreatic cancer cells (P < 0.05). At the same time, the levels of GSH, GPX4 and MMP were significantly decreased (P < 0.05). Ferrostatin-1 (Fer-1) combined with CSE could reverse CSE-mediated ferroptosis in pancreatic cancer cells (P < 0.05, 0.01). Conclusion CSE can inhibit the growth of pancreatic cancer cells by inducing GSH depletion and lipid peroxide accumulation, destroying intracellular redox balance and inducing ferroptosis.

R285.5

浙江省自然科学基金重点项目(LZ23H290001);国家自然科学基金项目(82474338,82274364,82174095);浙江中医药大学重点科研项目(2023JKZDZC07)