PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis

Zhang, Hai-Liang; Hu, Bingxin; Li, Zhiling; Du, Tian; Shan, Jia-Lu; Ye, Zhipeng; Peng, Xiaoxue; Li, Xuan; Huang, Yun; Zhu, Xianying; Chen, Yuhong; Gao, Feng; Yang, Dajun; Deng, Rong; Zhu, Xiao‐Feng

doi:10.1038/s41556-021-00818-3

Cited by 301 publications

(182 citation statements)

References 34 publications

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“…Genetic studies and preclinical disease models have clearly established that ferroptosis plays a critical role in acute tubular necrosis, particularly when it is induced by IRI [3][4][5]. The enzyme ACSL4 is involved in this process as a critical regulator that allows ferroptosis to proceed by supplying long unsaturated and easily oxidizable ω6 fatty acids to the plasma membrane [35,48,49]. This enzyme has also been established as a biomarker of ferroptosis, including in AKI [5,36,44].…”

Section: Discussionmentioning

confidence: 99%

Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury

Kolbrink

Samson-Himmelstjerna

Messtorff

et al. 2022

Cell. Mol. Life Sci.

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Ferroptosis, a type of iron-dependent programmed cell death distinct from apoptosis, necroptosis, and other types of cell death, is characterized by lipid peroxidation, reactive oxygen species production, and mitochondrial dysfunction. Accumulating evidence has highlighted vital roles for ferroptosis in multiple diseases, including acute kidney injury. Therefore, ferroptosis has become a major focus for translational research. However, despite its involvement in pathological conditions, there are no pharmacologic inhibitors of ferroptosis in clinical use. In the context of drug repurposing, a strategy for identifying new uses for approved drugs outside the original medical application, we discovered that vitamin K1 is an efficient inhibitor of ferroptosis. Our findings are strengthened by the fact that the vitamin K antagonist phenprocoumon significantly exacerbated ferroptotic cell death in vitro and also massively worsened the course of acute kidney injury in vivo, which is of utmost clinical importance. We therefore assign vitamin K1 a novel role in preventing ferroptotic cell death in acute tubular necrosis during acute kidney injury. Since the safety, tolerability, pharmacokinetics, and pharmacodynamics of vitamin K1 formulations are well documented, this drug is primed for clinical application, and provides a new strategy for pharmacological control of ferroptosis and diseases associated with this mode of cell death.

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Section: Discussionmentioning

confidence: 99%

Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury

Kolbrink

Samson-Himmelstjerna

Messtorff

et al. 2022

Cell. Mol. Life Sci.

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“…Because acyl-CoA synthetase 4 (ACSL4), which catalyzes the formation of acyl-CoA preferentially using arachidonate, executes ferroptosis, the incorporation of peroxidized PUFA into phospholipids, notably phosphatidylethanolamine, may promote ferroptosis [194,195]. Protein kinase CβII (PKCβII) reportedly senses lipid peroxidation products and activates ACSL4 by phosphorylation at specific threonine, which results in the incorporation of PUFA into phospholipids and the enhancement of lipid peroxidation in a positive-feedback manner [196]. Despite ex-tensive studies, however, the issue of how peroxidized phospholipids induce membrane destruction remains largely unknown [197].…”

Section: Roles Of Lipid Peroxidation In Ferroptosismentioning

confidence: 99%

Superoxide Radicals in the Execution of Cell Death

2022

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Superoxide is a primary oxygen radical that is produced when an oxygen molecule receives one electron. Superoxide dismutase (SOD) plays a primary role in the cellular defense against an oxidative insult by ROS. However, the resulting hydrogen peroxide is still reactive and, in the presence of free ferrous iron, may produce hydroxyl radicals and exacerbate diseases. Polyunsaturated fatty acids are the preferred target of hydroxyl radicals. Ferroptosis, a type of necrotic cell death induced by lipid peroxides in the presence of free iron, has attracted considerable interest because of its role in the pathogenesis of many diseases. Radical electrons, namely those released from mitochondrial electron transfer complexes, and those produced by enzymatic reactions, such as lipoxygenases, appear to cause lipid peroxidation. While GPX4 is the most potent anti-ferroptotic enzyme that is known to reduce lipid peroxides to alcohols, other antioxidative enzymes are also indirectly involved in protection against ferroptosis. Moreover, several low molecular weight compounds that include α-tocopherol, ascorbate, and nitric oxide also efficiently neutralize radical electrons, thereby suppressing ferroptosis. The removal of radical electrons in the early stages is of primary importance in protecting against ferroptosis and other diseases that are related to oxidative stress.

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“…Ferroptosis is a form of iron-dependent regulatory cell death distinguished from necrosis, apoptosis and autophagy ( 70 ), which can be triggered by the small-molecule compound erastin and RSL3 ( 71 , 72 ). Iron and polyunsaturated fatty acids (PUFAs) act as raw materials for lipid peroxidation to promote the occurrence of ferroptosis ( 73 , 74 ). While glutathione peroxidase 4 (GPX4) using glutathione (GSH) as the substrate effectively removes excess ROS through antioxidant mechanism and inhibits ferroptosis ( 75 ).…”

Section: Ferroptosis and Transporters In Malignant Brain Tumorsmentioning

confidence: 99%

Iron Transporters and Ferroptosis in Malignant Brain Tumors

et al. 2022

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Malignant brain tumors represent approximately 1.5% of all malignant tumors. The survival rate among patients is relatively low and the mortality rate of pediatric brain tumors ranks first among all childhood malignant tumors. At present malignant brain tumors remain incurable. Although some tumors can be treated with surgery and chemotherapy, new treatment strategies are urgent owing to the poor clinical prognosis. Iron is an essential trace element in many biological processes of the human body. Iron transporters play a crucial role in iron absorption and transport. Ferroptosis, an iron-dependent form of nonapoptotic cell death, is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism. Recently, compelling evidence has shown that inducing ferroptosis of tumor cells is a potential therapeutic strategy. In this review, we will briefly describe the significant regulatory factors of ferroptosis, iron, its absorption and transport under physiological conditions, especially the function of iron transporters. Then we will summarize the relevant mechanisms of ferroptosis and its role in malignant brain tumors, wherein the role of transporters is not to be ignored. Finally, we will introduce the current research progress in the treatment of malignant brain tumors by inducing ferroptosis in order to explain the current biological principles of potential treatment targets and treatment strategies for malignant brain tumors.

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PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis

Cited by 301 publications

References 34 publications

Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury

Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury

Superoxide Radicals in the Execution of Cell Death

Iron Transporters and Ferroptosis in Malignant Brain Tumors

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