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

铁凋亡是一种由铁依赖性脂质过氧化（LPO）驱动的细胞死亡类型。铁凋亡成为治疗癌症和退行性疾病的有吸引力的治疗靶点。铁凋亡的诱导与治疗耐药性肿瘤相关，而其抑制在解决退行性病变方面显示出有益作用。因此，在不同组织和病理条件下调节铁凋亡潜力的能力对于开发特异性治疗策略至关重要。许多研究清楚地表明，脂质代谢和细胞和组织脂质体的特定组成决定了铁凋亡的敏感性或抵抗性。在缺乏对脂质过氧化的充分控制的情况下，细胞膜富含PUFA的环境使细胞易于发生铁凋亡。此外，细胞发生铁凋亡性细胞死亡的承诺将取决于脂质氧化模式以及适应性脂质组重塑。奇怪的是，我们的知识脂质代谢作为一个关键的调节器的ferroptotic细胞死亡，来自遗传筛选和转录组学测量酶的表达水平，但不是从评估lipidome本身。为此，需要通过现代高分辨率脂质组学在脂质物质分子水平上更深入地了解脂质代谢和氧化，以预测铁凋亡敏感性并提出相关代谢途径作为促铁凋亡和抗铁凋亡治疗的潜在药理学靶点。 拟议的项目旨在扩大目前对脂质代谢在铁凋亡中的作用的理解，通过（1）在细胞和亚细胞水平上诱导和执行铁凋亡细胞死亡后绘制脂质体重塑和氧化的动态，以及（2）通过靶向脂质类和类型特异性途径探索脂质代谢的调节潜力。考虑到诱导和抑制铁凋亡用于治疗癌症和退行性疾病的双重利益，将解决癌症与正常细胞代谢的明显差异。最后，神经变性、急性肝损伤和肝细胞癌的体内模型将用于验证铁蛋白（oxi）脂质组学特征，并将其转化为临床应用。

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.