Synchronized renal tubular cell death involves ferroptosis

• DOI: 10.1073/pnas.1415518111
• Publication Date: 2014-11-11T04:42:34Z
• Authors: Andreas Linkermann; Rachid Skouta; Nina Himmerkus; Shrikant R. Mulay; Christin Dewitz; Federica De Zen; Agnes Prokai; Gabriele Zuchtriegel; Fritz Krombach; Patrick-Simon Welz; Ricardo Weinlich; Tom Vanden Berghe; Peter Vandenabeele; Manolis Pasparakis; Markus Bleich; Joel M. Weinberg; Christoph A. Reichel; Jan Hinrich Bräsen; Ulrich Kunzendorf; Hans-Joachim Anders; Brent R. Stockwell; Douglas R. Green; Stefan Krautwald
• Keywords: Cell death; 0301 basic medicine; 570; Caspase 8; 0303 health sciences; Physiology; Fas-Associated Death Domain Protein; Body Weight; 610; Apoptosis; Kidney tubules; 3. Good health; Mice; 03 medical and health sciences; Kidney Tubules; Receptor-Interacting Protein Serine-Threonine Kinases; Reperfusion Injury; FOS: Biological sciences; Pathology; Animals

Significance Cell death by regulated necrosis causes tremendous tissue damage in a wide variety of diseases, including myocardial infarction, stroke, sepsis, and ischemia–reperfusion injury upon solid organ transplantation. Here, we demonstrate that an iron-dependent form of regulated necrosis, referred to as ferroptosis, mediates regulated necrosis and synchronized death of functional units in diverse organs upon ischemia and other stimuli, thereby triggering a detrimental immune response. We developed a novel third-generation inhibitor of ferroptosis that is the first compound in this class that is stable in plasma and liver microsomes and that demonstrates high efficacy when supplied alone or in combination therapy.