Elucidating the relationship between lipid droplets, lipid metabolism, and lipotoxicity

铁下垂是脂毒性细胞死亡的一种调节形式，涉及铁依赖的产生 活性氧(ROS)与氧化损伤脂质(如脂质)的积累 过氧物)。铁下垂与退行性疾病的病因学有关，例如 与铁蓄积有关的神经变性。细胞包含一种保护途径，在这种途径中 谷胱甘肽依赖的过氧化物酶Gpx4修复过氧化脂质并阻止细胞死亡。 通过抑制Gpx4靶向诱导铁下垂已被证明是一种有效的治疗方法 体外和体内癌症模型，包括抗药性癌症。尽管 从这些最新的发现中，我们对潜在的机制的理解 上睑下垂仍然是有限的。此外，许多癌细胞对铁下垂有抵抗力，而且 癌症中铁下垂耐药的机制大多仍不清楚。要克服这一点 在知识的关键缺口，我们进行了合成致命的全基因组CRISPR筛查 确定保护癌细胞免受铁性下垂的因素。我们的发现确定了脂滴 氧化还原酶AIFM2是促进癌症耐受铁下垂的关键因素。删除 AIFM2显著增强细胞对铁性下垂的敏感性，AIFM2水平与癌症相关 对数百种癌细胞的耐药性，表明AIFM2是铁性下垂的生物标志物 耐药性，并表明它广泛地参与了许多类型的铁下垂耐药性 癌症的威胁。我们提出的研究建立在我们的发现基础上，并结合使用了 功能基因组、细胞生物学和生物化学策略，以实现以下目标：1) 阐明AIFM2预防脂质损伤和铁性下垂的机制，2)定义 脂滴、脂肪酸代谢和铁性下垂之间的关系，以及3)发现新的 保护癌细胞免受铁性下垂影响的因素。这些目标有可能是 具有变革性，因为他们关注的是癌细胞抵抗铁下垂的新机制 这与以谷胱甘肽为基础的典型保护系统并行。

Ferroptosis is a regulated form of lipotoxic cell death that involves iron-dependent generation of reactive oxygen species (ROS) and the accumulation of oxidatively damaged lipids (e.g. lipid peroxides). Ferroptosis has been implicated in the etiology of degenerative diseases, such as neurodegeneration associated with iron accumulation. Cells contain a protective pathway in which the glutathione-dependent peroxidase GPX4 repairs lipid peroxides and blocks cell death. Targeted induction of ferroptosis by inhibiting GPX4 has proven to be an efficacious treatment in in vitro and in vivo models of cancer, including drug-resistant forms of cancer. Despite the excitement from these recent findings, our understanding of the mechanisms underlying ferroptosis remains limited. Furthermore, many cancer cells are resistant to ferroptosis and the mechanisms of ferroptosis resistance in cancer remains mostly unknown. To overcome this critical gap in knowledge, we performed a synthetic lethal, whole-genome CRISPR screen to identify factors that protect cancer cells from ferroptosis. Our findings identify the lipid droplet oxidoreductase AIFM2 as a key factor that promotes ferroptosis resistance in cancer. Deletion of AIFM2 dramatically sensitizes cells to ferroptosis and AIFM2 levels correlate with cancer resistance across hundreds of cancer lines, indicating that AIFM2 is a biomarker of ferroptosis resistance and suggesting that it is broadly involved in ferroptosis resistance across many types of cancer. Our proposed research builds on our discovery and employs a combination of functional genomic, cell biology, and biochemistry strategies to achieve the following goals: 1) elucidate the mechanism by which AIFM2 prevents lipid damage and ferroptosis, 2) define the relationship between lipid droplets, fatty acid metabolism, and ferroptosis, and 3) identify new factors involved in protecting cancer cells from ferroptosis. These goals are potentially transformative because they focus on new mechanisms of ferroptosis resistance in cancer cells that act in parallel to the canonical glutathione-based protective system.