Cathepsin B is an executioner of ferroptosis

• Published in: Biochimica et biophysica acta. Molecular cell research 2021-03, Vol.1868 (3), p.118928-118928, Article 118928
• Main Authors: Nagakannan, Pandian, Islam, Md Imamul, Conrad, Marcus, Eftekharpour, Eftekhar
• Format: Article
• Language: English
• Subjects: Autophagy; Glutathione; GPX4; Histone H3; Lipid peroxidation; Lysosomes
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2020.118928

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. [Display omitted] •Lysosomal and mitochondrial integrity is compromised in ferroptosis.•Inhibition or knockout of cathepsin B protects against ferroptotic cell death.•Histone H3 is proteolytically cleaved during ferroptosis.•Cathepsin B functions as specific Histone H3 protease during ferroptosis.