Endocytosis is essential for cysteine-deprivation-induced ferroptosis Journal Article
| Authors: | Liu, X.; Zhao, Z.; Bian, Z.; Benthani, F. A.; Hu, Y.; Liang, D.; Jiang, X. |
| Article Title: | Endocytosis is essential for cysteine-deprivation-induced ferroptosis |
| Abstract: | <p>Ferroptosis is a form of cell death caused by iron-dependent phospholipid peroxidation and subsequent membrane rupture. Autophagic degradation of the iron-storage protein ferritin promotes ferroptosis by increasing cytosolic bioactive iron, presumably explaining how lysosomal inhibitors suppress ferroptosis. Surprisingly, we found that lysosomal inhibitors suppress cysteine-deprivat ion-induced (CDI) ferroptosis, even in autophagy-defective cells, and subsequently discovered that clathrin-mediated endocytosis (CME) of transferrin is essential for CDI ferroptosis. Blocking lysosomal proteolytic activity failed to inhibit ferroptosis, whereas disrupting endosomal acidification and eliminating the endocytic protein AP2M1 both impeded ferroptosis. Conversely, replenishing cellular iron with ferric ammonium citrate, but not with transferrin, restored CDI ferroptosis in endocytosis-deficient cells. Unexpectedly, abolishing endosomal acidification, CME, and the associated increase in cellular labile iron could not prevent ferroptosis triggered by direct inhibition of the ferroptosis-suppressing enzyme glutathione peroxidase-4 (GPX4). Together, this study reveals the essential role of endocytosis, specifically for CDI ferroptosis.</p> |
| Keywords: | iron; receptor; cell-death |
| Journal Title: | Molecular Cell |
| Volume: | 85 |
| Issue: | 17 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Publication status: | Published |
| Date Published: | 2025-09-04 |
| Online Publication Date: | 2025-08-25 |
| Start Page: | 3333 |
| End Page: | 3342.e4 |
| Language: | English |
| ACCESSION: | WOS:001568849600004 |
| DOI: | 10.1016/j.molcel.2025.08.006 |
| PROVIDER: | wos |
| PMCID: | PMC12416143 |
| PUBMED: | 40858109 |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Xuejun Jiang --Source: Wos |
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