Lysosomes are crucial organelles responsible for the degradation of cytosolic materials and bulky organelles, thereby facilitating nutrient recycling and cell survival. However, lysosome also acts as an executioner of cell death, including ferroptosis, a distinctive form of regulated cell death that hinges on iron-dependent phospholipid peroxidation. The initiation of ferroptosis necessitates three key components: substrates (membrane phospholipids enriched with polyunsaturated fatty acids), triggers (redox-active irons), and compromised defence mechanisms (GPX4-dependent and -independent antioxidant systems). Notably, iron assumes a pivotal role in ferroptotic cell death, particularly in the context of cancer, where iron and oncogenic signaling pathways reciprocally reinforce each other. Given the lysosomes’ central role in iron metabolism, various strategies have been devised to harness lysosome-mediated iron metabolism to induce ferroptosis. These include the re-mobilization of iron from intracellular storage sites such as ferritin complex and mitochondria through ferritinophagy and mitophagy, respectively. Additionally, transcriptional regulation of lysosomal and autophagy genes by TFEB enhances lysosomal function. Moreover, the induction of lysosomal iron overload can lead to lysosomal membrane permeabilization and subsequent cell death. Extensive screening and individually studies have explored pharmacological interventions using clinically available drugs and phytochemical agents. Furthermore, a drug delivery system involving ferritin-coated nanoparticles has been specifically tailored to target cancer cells overexpressing TFRC. With the rapid advancements in understandings the mechanistic underpinnings of ferroptosis and iron metabolism, it is increasingly evident that lysosomes represent a promising target for inducing ferroptosis and combating cancer.

中文翻译：

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靶向溶酶体诱导癌症铁死亡细胞的药理学方法

溶酶体是负责细胞质物质和大细胞器降解的重要细胞器，从而促进营养物循环和细胞存活。然而，溶酶体也充当细胞死亡的执行者，包括铁死亡，这是一种取决于铁依赖性磷脂过氧化的受调节细胞死亡的独特形式。铁死亡的启动需要三个关键组成部分：底物（富含多不饱和脂肪酸的膜磷脂）、触发器（氧化还原活性铁）和受损的防御机制（依赖于 GPX4 和不依赖于 GPX4 的抗氧化系统）。值得注意的是，铁在铁死亡细胞死亡中发挥着关键作用，特别是在癌症中，铁和致癌信号通路相互增强。鉴于溶酶体在铁代谢中的核心作用，人们设计了各种策略来利用溶酶体介导的铁代谢来诱导铁死亡。这些包括分别通过铁蛋白自噬和线粒体自噬从细胞内储存位点（例如铁蛋白复合物和线粒体）重新动员铁。此外，TFEB 对溶酶体和自噬基因的转录调节可增强溶酶体功能。此外，溶酶体铁超载的诱导可导致溶酶体膜透化和随后的细胞死亡。广泛的筛选和单独研究已经探索了使用临床可用药物和植物化学制剂的药理学干预措施。此外，涉及铁蛋白涂层纳米粒子的药物输送系统专门针对过度表达 TFRC 的癌细胞而定制。随着对铁死亡和铁代谢机制基础的了解的快速进展，越来越明显的是，溶酶体代表了诱导铁死亡和抗癌的有希望的靶标。