ALOX15-launched PUFA-phospholipids peroxidation increases the susceptibility of ferroptosis in ischemia-induced myocardial damage

Ma, Xiaojing; Liu, Jiang-Han-Zi; Liu, Chunyu; Sun, Wanyang; Duan, Wen-Jun; Wang, Guan; Kojima, Hiroshi; He, Rong‐Rong; Li, Yi-Fang; Yang, Chen

doi:10.1038/s41392-022-01090-z

Cited by 109 publications

(48 citation statements)

References 64 publications

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“…With the exception of 15‐LOX that also accepts membrane phospholipids, human LOX isoenzymes (5‐LOX, 12‐LOX) are limited to nonesterified PUFAs as substrates 11 . In addition to 15‐LOX, 35 cytochrome P450 oxidoreductase and NADH‐cytochrome b5 reductase 1 participate in enzymatic membrane peroxidation during ferroptosis 18,36 . Nonenzymatic peroxidation of membrane‐bound PUFAs, on the other hand, is associated with the availability of free redox‐active metal ions, that is, ferrous iron, that converts hydrogen and alkyl peroxides into hydroxyl and alkoxy radicals via the Fenton reaction, respectively 5 .…”

Section: Potential Targets In Ferroptosis Related To Redox Signalingmentioning

confidence: 99%

Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

Koeberle

Kipp

Stuppner

et al. 2023

Medicinal Research Reviews

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Ferroptosis is an iron-dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions and structural features of ferroptosis-inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic, and therapyresistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosisinducing small molecules that target central players in ferroptosis. Focus is placed on (i) glutathione peroxidase (GPX) 4, the only GPX isoenzyme that detoxifies complex membrane-bound lipid hydroperoxides, (ii) the cystine/ glutamate antiporter system X c − that is central for glutathione regeneration, (iii) the redox-protective transcription factor nuclear factor erythroid 2-related factor (NRF2), and (iv) GPX4 repression in combination with induced heme degradation via heme oxygenase-1. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as

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Section: Potential Targets In Ferroptosis Related To Redox Signalingmentioning

confidence: 99%

Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

Koeberle

Kipp

Stuppner

et al. 2023

Medicinal Research Reviews

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“…During ischemia, specific redox reactions of PUFA-phospholipids in cardiomyocytes are induced, which act as initiating signals to trigger intensive oxidative damage during the reperfusion phase. ALOX15, a critical enzyme for the oxidation of PUFA-phospholipids, is induced by ischemia/hypoxia [ 60 ]. The induction of ALOX15 functions as a “burning point” and initiates the oxidation of PUFA-phospholipids, particularly PUFA-PE, resulting in ferroptosis in myocardial cells.…”

Section: Mechanisms and Targeted Therapies For Ferroptosis In Irimentioning

confidence: 99%

Ferroptosis—A New Dawn in the Treatment of Organ Ischemia–Reperfusion Injury

Zhou

Han

Guo

et al. 2022

Cells

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Ischemia–reperfusion (I/R) is a common pathological phenomenon that occurs in numerous organs and diseases. It generally results from secondary damage caused by the recovery of blood flow and reoxygenation, followed by ischemia of organ tissues, which is often accompanied by severe cellular damage and death. Currently, effective treatments for I/R injury (IRI) are limited. Ferroptosis, a new type of regulated cell death (RCD), is characterized by iron overload and iron-dependent lipid peroxidation. Mounting evidence has indicated a close relationship between ferroptosis and IRI. Ferroptosis plays a significantly detrimental role in the progression of IRI, and targeting ferroptosis may be a promising approach for treatment of IRI. Considering the substantial progress made in the study of ferroptosis in IRI, in this review, we summarize the pathological mechanisms and therapeutic targets of ferroptosis in IRI.

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“…The early ischemic stage, a disorder of PUFAs-phospholipids, may initiate peroxidative conditions, providing a priming signal for oxidative injury in the reperfusion stage. Studies have found that oxidative phosphorylation of the core enzyme ALOX15 can initiate PUFA-phospholipid peroxidation and enhance the susceptibility to ferroptosis in ischemia-induced myocardial injury ( 31 ). Consequently, inhibiting ferroptosis during the early stage of ischemia can reduce myocardial injury caused by reperfusion as soon as possible.…”

Section: Ferroptosis In Cardiovascular Diseasementioning

confidence: 99%

Research progress on the role of ferroptosis in cardiovascular disease

Xie

Yang

2022

Front. Cardiovasc. Med.

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The cardiovascular disease pathogenesis is extremely complex and seriously threatens human health. Cardiomyocyte death plays a significant role in cardiovascular disease occurrence and development. In addition to the previously revealed modes of cell death (apoptosis, autophagy, and pyroptosis), ferroptosis is highly related to the development of cardiovascular diseases, including arrhythmia, atherosclerosis, and myocardial ischemia/reperfusion. Ferroptosis is a novel cell death pathway driven by lipid peroxidation and iron overload. Lipid, amino acid, and iron metabolism regulate the ferroptosis pathway. Small molecule compounds (iron chelators, antioxidants, and ferroptosis inhibitors) and genetic programming can alleviate or prevent cardiovascular disease by inhibiting the ferroptosis pathway. Ferroptosis plays a key role in various cardiovascular disease occurrence and development, and inhibiting ferroptosis in cardiomyocytes is expected to become a feasible treatment method. In this mini-review, we systematically summarize the molecular mechanisms of ferroptosis in different cardiovascular diseases, delineate the regulatory network between ferroptosis and cardiovascular diseases, and highlight its potential therapeutic targets.

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ALOX15-launched PUFA-phospholipids peroxidation increases the susceptibility of ferroptosis in ischemia-induced myocardial damage

Cited by 109 publications

References 64 publications

Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

Ferroptosis—A New Dawn in the Treatment of Organ Ischemia–Reperfusion Injury

Research progress on the role of ferroptosis in cardiovascular disease

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