Details

Autor(en) / Beteiligte

• Feng, Ji
• Wang, Zi-Xuan
• Bin, Jin-Lian
• Chen, Yong-Xin
• Ma, Jing
• Deng, Jing-Huan
• Huang, Xiao-Wei
• Zhou, Jing
• Lu, Guo-Dong

Titel

Pharmacological approaches for targeting lysosomes to induce ferroptotic cell death in cancer

Ist Teil von

• Cancer letters, 2024-04, Vol.587, p.216728-216728, Article 216728

Ort / Verlag

Ireland: Elsevier B.V

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Lysosome-mediated iron metabolism is a promising target to trigger ferroptosis in cancer. Accordingly, pharmacological strategies have been developed to promote ferroptosis through ferritinophagy, TFEB-involved lysosome activation and lysosome iron overload. [Display omitted] •Lysosomes have distinct functions in autophagy and cell death processes.•Lysosome is a promising target for inducing ferroptosis by modulating iron metabolism in cancer cells.•Targeting lysosomes via ferritinophagy, TFEB activation, and lysosomal iron overload offers new avenues for cancer treatment.•Utilizing ferritin-coated nanoparticles to deliver drugs to TFR1-expressing cancer cells shows promise in targeted therapy.