Cathepsin B is an executioner of ferroptosis.
Ferroptosis is a necrotic form of cell death caused by inactivation of the glutathione system and uncontrolled iron-mediated lipid peroxidation. Increasing evidence implicates ferroptosis in a wide range of diseases from neurotrauma to cancer, highlighting the importance of identifying an executioner system that can be exploited for clinical applications. In this study, using pharmacological and genetic models of ferroptosis, we observed that lysosomal membrane permeabilization and cytoplasmic leakage of cathepsin B unleashes structural and functional changes in mitochondria and promotes a not previously reported cleavage of histone H3. Inhibition of cathepsin-B robustly rescued cellular membrane integrity and chromatin degradation. We show that these protective effects are independent of glutathione peroxidase-4 and are mediated by preventing lysosomal membrane damage. This was further confirmed when cathepsin B knockout primary fibroblasts remained unaffected in response to various ferroptosis inducers. Our work identifies new and yet-unrecognized aspects of ferroptosis and identifies cathepsin B as a mediator of ferroptotic cell death.
['Nagakannan|Pandian|P|', 'Islam|Md Imamul|MI|', 'Conrad|Marcus|M|', 'Eftekharpour|Eftekhar|E|']
D000818:Animals D002401:Cathepsin B D002460:Cell Line D000079403:Ferroptosis D055785:Gene Knockdown Techniques D006657:Histones D015227:Lipid Peroxidation D008247:Lysosomes D053078:Membrane Potential, Mitochondrial D051379:Mice D008928:Mitochondria D041681:NIH 3T3 Cells D009474:Neurons
Glutathione Lipid peroxidation Lysosomes Histone H3 Autophagy GPX4