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Necroptosis inhibitors: mechanisms of action and therapeutic potential

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Abstract

Necroptosis is a type of programmed cell death that is morphologically similar to necrosis. This type of cell death is involved in various pathophysiological disorders, including inflammatory, neurodegenerative, infectious, and malignant diseases. Receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) pseudokinase constitute the core components of the necroptosis signaling pathway and are considered the most promising targets for therapeutic intervention. The discovery and characterization of necroptosis inhibitors not only accelerate our understanding of the necroptosis signaling pathway but also provide important drug candidates for the treatment of necroptosis-related diseases. Here, we will review recent research progress on necroptosis inhibitors, mechanisms of action and their potential applications for disease treatment.

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Abbreviations

PCD:

Programmed cell death

RIPK1:

Receptor-interacting protein kinase 1

RIPK3:

Receptor-interacting protein kinase 3

MLKL:

Mixed lineage kinase domain-like protein

TNF:

Tumor necrosis factor

TLR:

Toll-like receptor

IFNAR:

Interferon receptors

ZBP1:

Z-DNA binding protein 1

TNFR1:

TNF receptor 1

TRADD:

TNFR1-associated death domain protein

cIAP1/2:

Cellular inhibitor of apoptosis proteins 1 and 2

TRAF2/5:

Tumor necrosis factor receptor-associated factor 2/5

TAK1:

Transforming growth factor-β-activated kinase 1

IKK:

IκB kinase

SMAC:

Second mitochondria-derived activator of caspase

CYLD:

Cylindromatosis

FADD:

Fas-associated death domain protein

RHIM:

RIP homotypic interaction motif

TRIF:

TIR-domain-containing adapter-inducing interferon-β

Nec-1:

Necrostatin-1

IDO:

Indoleamine 2,3-dioxygenase

AKI:

Acute kidney injury

AAA:

Abdominal aortic aneurysm

PDGFRα:

Platelet-derived growth factor receptor α

SIRS:

Systemic inflammatory response syndrome

PERK:

Protein kinase R-like ER kinase

AurK:

Pan-Aurora kinase

IECs:

Intestinal epithelial cells

PK:

Pharmacokinetic

EAE:

Experimental autoimmune encephalomyelitis

MS:

Multiple sclerosis

IMIDs:

Inflammatory illnesses

CNS:

Central nervous system

AD:

Alzheimer disease

ALS:

Amyotrophic lateral sclerosis

FIH:

First-in-human

IC50:

Half maximal inhibitory concentration

LDH:

Lactate dehydrogenase

mPTP:

Mitochondrial permeability transition pore

H/R:

Hypoxia/reoxygenation

NSA:

Necrosulfonamide

SAR:

Structure–activity relationship

HSP90:

Heat shock protein 90

GA:

Geldanamycin

17AAG:

17-Allylamino-17-desmethoxygeldanamycin

KA:

Kongensin A

6,7-DHC:

6,7-Dihydroxycoumarin

CKD:

Chronic kidney disease

PKIS:

Published kinase inhibitor set

FN3:

Fibronectin type III

4HB:

Four-helix bundle

NBC1:

Necroptosis-blocking compound 1

PROTAC:

Proteolysis targeting chimeric technology

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Acknowledgements

This work was supported by grants from Tongji University Students Innovation Training Program (No. X2022212), the National Natural Science Foundation of China (No. 32170748), the Shanghai Committee of Science and Technology (No. 21490714300), the Key Research and Development Program of Ningxia (No. 2022BFH02012) and the Fundamental Research Funds for the Central Universities.

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Authors and Affiliations

  1. School of Medicine, Tongji University, Shanghai, 200092, China

    Yingbo Zhou, Zhangtao Cai, Yijia Zhai, Jintao Yu & Zhenyu Cai

  2. School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China

    Qiujing He

  3. Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200092, China

    Yuan He & Zhenyu Cai

  4. Center of Excellence for Cancer and Inflammation, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand

    Siriporn Jitkaew

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  1. Yingbo Zhou
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ZC had the idea for the review article. YZ, ZC, QH, JY, YZ and YH performed the literature search. YZ, ZC, QH, JY, YZ and YH drafted the manuscript. ZC critically revised the manuscript.

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Correspondence to Zhenyu Cai.

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Zhou, Y., Cai, Z., Zhai, Y. et al. Necroptosis inhibitors: mechanisms of action and therapeutic potential. Apoptosis 29, 22–44 (2024). https://doi.org/10.1007/s10495-023-01905-6

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