Molecular cellAug 26, 2025

Cell intake process is needed for cell death caused by cysteine loss

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 20, 2026

Abstract

Lysosomal inhibitors suppress cysteine-deprivation-induced ferroptosis even in autophagy-defective cells.

Ferroptosis is linked to the breakdown of iron-dependent lipids, leading to cell death.
Autophagic degradation of ferritin increases bioactive iron, which may promote ferroptosis.
Clathrin-mediated endocytosis of transferrin is necessary for cysteine-deprivation-induced ferroptosis.
Blocking endosomal acidification and the endocytic protein AP2M1 disrupts ferroptosis.
Restoring cellular iron with ferric ammonium citrate can reinstate ferroptosis in cells lacking endocytosis.
Direct inhibition of the enzyme glutathione peroxidase-4 does not require endocytosis or increased cellular iron to trigger ferroptosis.

Simplified

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-deprivation-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.