脂质代谢介导的铁死亡在肿瘤进展中的作用及机制  

Role and Mechanism of Lipid Metabolism-mediated Ferroptosis in the Progression of Tumors

作　　者：张了 罗再 黄陈 ZHANG Liao;LUO Zai;HUANG Chen(Department of Gastrointestinal Surgery,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China)

机构地区：[1]上海交通大学医学院附属第一人民医院胃肠外科,上海200080

出　　处：《中国生物化学与分子生物学报》2025年第3期353-363,共11页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金面上项目(No.82072662);上海交通大学“交大之星”计划医工交叉研究基金;东方英才计划拔尖项目(2023);上海市青年科技英才扬帆计划(No.24YF2734700)资助。

摘　　要：铁死亡是一种以依赖铁的脂质过氧化为核心的新型程序性细胞死亡形式。多种代谢物可参与铁死亡的调控,其中脂质代谢发挥着重要作用。含多不饱和脂肪酸的磷脂(phospholipids containing polyunsaturated fatty acyl chain,PUFA-PLs)在生物膜上发生超阈值的过氧化,导致膜结构和功能的破坏是最为经典的脂质代谢介导的铁死亡机制。此外,含多不饱和脂肪酸(polyunsaturated fatty acid,PUFA)的特殊脂质,例如具有二酰基-PUFA尾的磷脂(phospholipid with diacyl-PUFA tails,PL-PUFA 2)、多不饱和醚磷酯(polyunsaturated ether phospholipid,PUFA-ePL)、含PUFA的胆固醇酯(cholesterol ester containing polyunsaturated fatty acyl chain,PUFA-CE)也被发现,可通过提供PUFA用于过氧化,进而参与铁死亡过程;脂滴通过储存和释放PUFA调节铁死亡的敏感性;胆固醇代谢的中间产物及衍生物主要参与铁死亡的负向调控;不同类别的鞘脂对铁死亡的调控方向并不一致。基于前期大量研究证实,铁死亡与胃肠肿瘤的增殖、转移和耐药的发生等密切相关,我们进一步归纳了胃肠肿瘤细胞中驱动铁死亡抵抗的相关脂质代谢机制,如削弱PUFA-PLs合成代谢及过氧化进程,增强铁死亡防御系统等,以及胆固醇代谢、脂滴代谢、鞘脂类代谢与胃肠肿瘤产生铁死亡抗性的关系。靶向这些特定脂质及代谢酶与途径以调控铁死亡具有重要的临床潜在价值,有望为寻找新的胃肠肿瘤诊断、预后标志物和治疗药物,及逆转化疗耐药提供新思路。Ferroptosis is a new form of programmed cell death with iron-dependent lipid peroxidation as its core.A variety of metabolites are involved in the regulation of ferroptosis,among which lipid metabolism plays an important role.The most classic lipid metabolism-mediated ferroptosis mechanism is that phospholipids containing polyunsaturated fatty acyl chain(PUFA-PLs)located on biological membranes undergo super-threshold peroxidation,which leads to the destruction of membrane structure and function.In addition,special lipids containing polyunsaturated fatty acid(PUFA),such as phospholipid with diacyl-PUFA tails(PL-PUFA 2),polyunsaturated ether phospholipid(PUFA-ePL),cholesterol ester containing polyunsaturated fatty acyl chain(PUFA-CE)have also been found to be involved in the ferroptosis process by providing PUFA for peroxidation.Lipid droplets was also found to regulate the sensitivity of ferroptosis through storing and releasing PUFA.Intermediates and derivatives of cholesterol metabolism are mainly involved in the negative regulation of ferroptosis,whereas different classes of sphingolipids were reported to have inconsistent regulatory directions for ferroptosis.A large number of previous studies have confirmed that ferroptosis is closely related to the metastasis and drug resistance of gastrointestinal tumors,therefore,we further summarized the lipid metabolism mechanisms related to ferroptosis resistance in gastrointestinal tumor cells,such as weakening the anabolism and peroxidation processes of PUFA-PLs,enhancing the ferroptosis defense system and so on.At the same time,we elaborated on the relationship between cholesterol metabolism,lipid drop metabolism,sphingolipid metabolism,and ferroptosis resistance in gastrointestinal tumors.Targeting these specific lipids,metabolic enzymes,and pathways to regulate ferroptosis has important clinical potential value.It is expected to provide new ideas for finding new diagnostic and prognostic markers,therapeutic drugs,and reversing chemotherapy resistance for gastroint

关 键 词：铁死亡 脂质代谢 胃癌 结直肠癌 

分 类 号：Q25[生物学—细胞生物学]