Non-classical ferroptosis inhibition by a small molecule targeting PHB2

Yang, Wei; Mu, Bo; You, Jianxin; Tian, Chuanshan; Bin, Huachao; Xu, Zhiqiang; Zhang, Liting; Ma, Ronggang; Wu, Ming; Zhang, Guo; Huang, Chong; Li, Linli; Shao, Zhenhua; Dai, Lunzhi; Désaubry, Laurent; Yang, Shengyong

doi:10.1038/s41467-022-35294-2

Cited by 24 publications

(10 citation statements)

References 66 publications

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“…Among them, Hnrnpc and Phb2 have been reported to promote ferroptosis thus downregulation in DOX treatment did not fit with our hypothesis. [ 27,28 ] No evidence of ferroptosis nor iron homeostasis were found for Rps9, Rpl5, Prkaca, and Psmb3. Park7 was chosen for further characterization for its ability to stabilize and increase intracellular FeS cluster levels in prokaryotic systems.…”

Section: Resultsmentioning

confidence: 99%

The Imbalance of p53–Park7 Signaling Axis Induces Iron Homeostasis Dysfunction in Doxorubicin‐Challenged Cardiomyocytes

et al. 2023

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Doxorubicin (DOX)‐induced cardiotoxicity (DoIC) is a major side effect for cancer patients. Recently, ferroptosis, triggered by iron overload, is demonstrated to play a role in DoIC. How iron homeostasis is dysregulated in DoIC remains to be elucidated. Here, the authors demonstrate that DOX challenge exhibits reduced contractile function and induction of ferroptosis‐related phenotype in cardiomyocytes, evidenced by iron overload, lipid peroxide accumulation, and mitochondrial dysfunction. Compared to Ferric ammonium citrate (FAC) induced secondary iron overload, DOX‐challenged cardiomyocytes show a dysfunction of iron homeostasis, with decreased cytoplasmic and mitochondrial iron–sulfur (FeS) cluster‐mediated aconitase activity and abnormal expression of iron homeostasis–related proteins. Mechanistically, mass spectrometry analysis identified DOX‐treatment induces p53‐dependent degradation of Parkinsonism associated deglycase (Park7) which results in iron homeostasis dysregulation. Park7 counteracts iron overload by regulating iron regulatory protein family transcription while blocking mitochondrial iron uptake. Knockout of p53 or overexpression of Park7 in cardiomyocytes remarkably restores the activity of FeS cluster and iron homeostasis, inhibits ferroptosis, and rescues cardiac function in DOX treated animals. These results demonstrate that the iron homeostasis plays a key role in DoIC ferroptosis. Targeting of the newly identified p53–Park7 signaling axis may provide a new approach to prevent DoIC.

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Section: Resultsmentioning

confidence: 99%

The Imbalance of p53–Park7 Signaling Axis Induces Iron Homeostasis Dysfunction in Doxorubicin‐Challenged Cardiomyocytes

et al. 2023

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“…DARTS is a universally applicable target identification approach that analyzes direct drug binding to targets (49), which requires no modification of the drug and is independent of any biological effects of the drug (50)(51)(52). In our research, we performed DARTS to reveal the potential target of NU6300 account for the antipyroptotic effects.…”

Section: Discussionmentioning

confidence: 99%

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation

Jiang,

Zhang,

Cai

et al. 2024

Sci. Adv.

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Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate–induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.

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“…Yang et al screened a non-classical inhibitor of ferroptosis, YL-939 , from chemical libraries. They found that YL-939 binds to its target inhibitor 2PHB2 and promotes ferritin expression to reduce iron levels to inhibit ferroptosis and alleviate ferroptosis-mediated liver injury ( Yang et al, 2022 ). Compound YL-939 provides a new intervention strategy for diseases associated with ferroptosis.…”

Section: Small Molecule Ferroptosis Inhibitorsmentioning

confidence: 99%

Ferroptosis inhibitors: past, present and future

Zhang,

Luo,

Xiang

et al. 2024

Front. Pharmacol.

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Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery.

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Non-classical ferroptosis inhibition by a small molecule targeting PHB2

Cited by 24 publications

References 66 publications

The Imbalance of p53–Park7 Signaling Axis Induces Iron Homeostasis Dysfunction in Doxorubicin‐Challenged Cardiomyocytes

The Imbalance of p53–Park7 Signaling Axis Induces Iron Homeostasis Dysfunction in Doxorubicin‐Challenged Cardiomyocytes

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation

Ferroptosis inhibitors: past, present and future

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