Understanding dynamics of lipid metabolism and oxidation in ferroptotic cell death programme

铁下垂是一种由铁依赖的脂质过氧化(LPO)引起的细胞死亡。铁下垂成为治疗癌症和退行性疾病的一个有吸引力的治疗靶点。铁下垂的诱导与耐药肿瘤的治疗有关，而抑制铁下垂在治疗退行性病变方面显示出有益的效果。因此，能够在不同的组织和病理条件下调节铁性下垂的潜力对于开发特定的治疗策略是至关重要的。大量研究清楚地表明，脂类代谢和细胞和组织脂体的特定组成决定了铁下垂的敏感性或抵抗力。富含多不饱和脂肪酸的细胞膜环境，在缺乏对脂质过氧化的充分控制的情况下，容易使细胞发生铁下垂。此外，细胞对铁性细胞死亡的承诺将取决于脂类氧化模式和适应性脂体重塑。奇怪的是，我们关于脂代谢作为铁链细胞死亡的关键调节因子的知识，来自于对酶表达水平的遗传筛选和转录测量，而不是来自于对脂体本身的评估。为此，现代高分辨脂质组学需要在脂质物种分子水平上更深入地了解脂质代谢和氧化，以预测铁下垂的敏感性，并提出相关的代谢途径，作为促进和抗铁下垂治疗的潜在药理靶点。该项目旨在通过(1)在细胞和亚细胞水平上绘制脂小体重塑和氧化的动力学图谱，以及(2)通过靶向脂类和类型特异性通路来探索脂代谢的调节潜力，以扩大目前对脂代谢在铁下垂中作用的理解。考虑到在治疗癌症和退行性疾病中诱导和抑制铁下垂的双重兴趣，癌症和正常细胞在代谢方面的明显差异将被解决。最后，神经变性、急性肝损伤和肝细胞癌的体内模型将被用来验证铁链(OXI)脂质组学特征，并访问它们进入临床应用的潜力。

Ferroptosis is a type of cell death driven by iron-dependent lipid peroxidation (LPO). Ferroptosis emerged as an attractive therapeutic target for treating cancer and degenerative diseases. Induction of ferroptosis is relevant for the treatment of therapy-resistant tumors whereas its inhibition showed beneficial effects in addressing degenerative pathologies. Thus, ability to modulate ferroptosis potential in different tissues and pathological conditions is utmost importance for the development of specific therapeutic strategies. Numerous studies clearly established that lipid metabolism and specific composition of cellular and tissue lipidomes determine ferroptosis sensitivity or resistance. PUFA-rich environment of cellular membranes, in the absence of adequate control over lipid peroxidation, predispose cells towards ferroptosis. Moreover, commitment of a cell to undergo ferroptotic cell death will depend on lipid oxidation patterns as well as adaptive lipidome remodeling. Curiously, our knowledge on lipid metabolism as a key regulator of ferroptotic cell death, derived from genetic screens and transcriptomics measurements of enzymes expression levels but not from assessment of lipidome itself. To this end, a deeper understanding of lipid metabolism and oxidation at lipid species molecular level, provided by modern high resolution lipidomics, is required to predict ferroptosis sensitivity and propose relevant metabolic pathways as a potential pharmacological targets for pro- and anti-ferroptotic therapies. The proposed project aims to expand current understanding on the role of lipid metabolism in ferroptosis by (1) mapping dynamics of lipidome remodeling and oxidation upon induction and execution of ferroptotic cell death at cellular and subcellular levels, and (2) exploring modulatory potential of lipid metabolism by targeting lipid class and type specific pathways. Considering dual interest in induction and inhibition of ferroptosis for treating cancer and degenerative disorders, apparent differences in metabolism of cancer vs normal cells will be addresses. Finally, in vivo models of neurodegeneration, acute liver injury and hepatocellular carcinomas will be used to validate ferroptotic (oxi)lipidomics signatures and access their translational potential into clinical applications.