title: Ferroptosis: process and function.
abstract: Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kang
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.|Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: D
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D016923:Cell Death; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007501:Iron / Q000502:physiology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; D007501:Iron