Ferroptosis: 질병과의 메커니즘 및 연결

2021

Ferroptosis: mechanisms and links with diseases

https://www.nature.com/articles/s41392-020-00428-9

 

그림 2: ferroptosis의 신호 전달 경로에 대한 도식적 설명.

 

 

표시된 경로는 지질 ROS 생성을 통해 ferroptosis 감도를 제어합니다. 포스파티딜에탄올아민(PE); 인지질(PL-H); 인지질 알콕실 라디칼(PL-O·); 인지질 퍼옥실 라디칼(PL-OO·); 인지질 하이드로퍼옥사이드(PL-OOH); 트랜스페린(TF). 그림에 사용된 기호에는 생체 분자의 이름이 표시되어 있습니다.

그림 3: 페로프토시스 방지 경로의 개요.

 

 

 

ferroptosis, GSH 의존성 GPx4 경로 및 NADPH 의존성 FSP1 경로에서 확인된 두 가지 방어 메커니즘에 대한 도식적 설명. 글루타민(Gln); 글루타메이트(Glu); 시스테인(Cys); 글리신(Gly); 글루타티온-이황화물 환원효소(GSR); 자극 단백질 1 및 3(SP1/3); 핵인자 Y(NF-Y); cAMP-반응 요소 조절제-타우(CREM-타우); 초기 성장 반응 단백질 1(EGR1); 핵인자 κB(NF-κB); 스테롤 조절 결합 요소 1(SREBP1).

 

Table 1 Summary of ferroptosis inducers.

 

Compound/drug               Target                   Mechanism                                          Model

Erastin	System Xc−	Interfere cystine uptake and deplete GSH, increase LIP level	Cell line: HT-1080, SH-SY5Y
Piperazine erastin	System Xc−	Upregulate PTGS2, suppressed by vitamin E	BJeLR cells
Imidazole ketone erastin	System Xc−	Interfere cystine uptake and deplete GSH	Cell line: G-401, DLBCL xenograft model
Sulfasalazine	System Xc−	Interfere cystine uptake and deplete GSH	Nb2 lymphoma cells
Sorafenib	System Xc−	Blocks system Xc− and deplete GSH	HCC cells
Glutamate	System Xc−	Interfere cystine uptake and deplete GSH	HT-1080 cells
BSO (buthionine sulfoximine)	Glutamate-cysteine ligase	Mediate glutathione deficiency	Newborn rats
DPI2		Interfere cystine uptake and deplete GSH	BJeLR cells
Cyst(e)inase	Cysteine consumption	Deplete L-Cysteine via interfering transsulfuration pathway and/or increasing ROS production	PCa cells, FVB/N mice
BAY 87-2243	Mitochondrial complex I	Suppress the activity of Mitochondrial complex I, increase ROS	Cell line: H460, G361 and SK-MEL-28
Artesunate	Nrf2− antioxidant response element	Downregulate GSH level, upregulate lipid ROS and mediate ferritinophagy	Cell line: HNC, LX-2; ICR mice,
(1S,3R)-RSL3	GPX4	Inhibit the activity of GPX4 via binding selenocysteines at active-site	Cell line: BJeLR, HT-1080
ML162, ML210, DPI 7, DPI 10, DPI 12, DPI 13, DPI 17, DPI 18, DPI 19	GPX4	Inhibit the activity of GPX4	BJeLR cells
Altretamine	GPX4	Inhibit the activity of GPX4	U-2932 cells
Withaferin A	GPX4 and KEAP1 inactivation	Stimulate Nrf2 via binding KEAP1, inhibit GPX4	IMR-32 and SK-N-SH cells
FIN56	GPX4 and squalene synthase	Increase degradation of GPX4, suppress CoQ10 via targeting and stimulating SQS	Cell line: BJeLR, HT-1080, PACN1, MEFs
Statins (fluvastatin, lovastatin, simvastatin)	HMGCR	Inhibit HMGCR and suppress GPX4 biosynthesis	Cell line: HT-1080, HCC4006
Hemoglobin		Release iron and produce lethal ROS	Cell line: OHSCs
Hemin		Cause high level of HMOX1 and increase intracellular iron	Cell line: IMR-32, HT22, primary cortical neurons; Male Swiss albino mice
FeCl2, (NH4)2Fe(SO4)2		Release iron and produce lethal ROS	Cell line: IMR-32, OHSCs
Non-thermal plasma	Ferritin	Break ferritin and induce reduction from Fe(III) to Fe(II)	Cell line: IMR-90-SV, SAS, Ca9-22
Salinomycin, ironomycin	DMT1, ferritin, GPX4	Decrease expression of GPX4 and ferritin, and inhibit DMT1 by interrupting lysosomal iron translocation	Cell line: BCSCs, CSC
Siramesine + lapatinib	Iron transport	Increase transferrin and decrease ferroportin	Cell line: MDA MB 231, MCF-7, ZR-75, SKBr3, A549, U87
FINO2 (1,2-dioxolane)	Lipid	Inactivate GPX4 and lead to Fe(III) oxidation	Cell line: IGROV-1, NCI-H322 M, NCI60, BJ-hTERT
BAY 11-7085	IκBα	Increase HO-1 related to redox regulation	Cell line: MCF-7, MDA-MB-231, MDA-MB-468, SKBR3
Trigonelline,brusatol	NRF2	Inhibit Nrf2	Cell line: HNC, HNSCC
Artemisinin derivatives		Induce ROS and mediate oxidative stress	CCRF-CEM cells
CIL41, CIL56, CIL69, CIL70, CIL75, CIL79		Induce ROS(CIL56 mediate ferroptosis at low concentration while necrotic, non-suppressible phenotype at high)	Cell line:BJ cells, HT-1080

Table 2 Summary of ferroptosis inhibitors.

Compound/drug                 Target                     Mechanism                       Model

Vitamin E, α-toc, trolox, tocotrienols	LOX	Restrain LOX PUFA oxygenation	Cell line: PBMCs, Pfal1; Gpx4 KO C57BL/6J mice
Deuterated polyunsaturated fatty acid	Lipid peroxidation	Inhibit lipid peroxidation	APP/PS1 mice
Butylated hydroxytoluene, butylated hydroxyanisole	Lipid peroxidation	Inhibit lipid peroxidation	C57BL/6J mice
Ferrostatins, liproxstatins	Lipid peroxidation	Inhibit lipid peroxidation	Cell line: HEK-29, HT22, HT-1080
CoQ10, idebenone	Lipid peroxidation	Target lipid peroxyl radicals	Cell line: HT1080, Pfa1, NCI-H460, NCI-H2291, NCI-H1703 and NCI-H446
XJB-5-131, JP4-039	Lipid peroxidation	Nitroxide-based mitochondrial lipid peroxidation mitigators	Cell line: HT-1080, BJeLR, and panc-1 cells
Baicalein	LOX	Inhibit 12/15-LOX	HT22 cells, TBI mice model
PD-146176	LOX	Inhibit 15-LOX-1	HEK-293 cells
AA-861	LOX	Inhibit 5-LOX	HEK-293T cells; ALF rat
Zileuton	LOX	Inhibit 5-LOX	Cell line: LNCaP, K562, HT22
Deferoxamine, ciclopirox, deferiprone	Iron	Reduce intracellular iron	HT-1080
Glutamine deprivation, glutaminolysis inhibitor	Glutaminolysis	Maybe hinder mitochondrial TCA cycle	Cell line: HT-1080, MEFs
Cycloheximide	Protein synthesis	Inhibit xCT protein synthesis	Primary cortical neurons
β-mercaptoethanol	Reducing agent	Reduce Cys2 to Cys	OT-1 CD8þ T cell
Dopamine	Neurotransmitter	Increase the stability of GPX4	Cell line: PANC1, HEY, MEF, HEK293
Selenium	Selenoproteins	Enhance the number of selenoproteins	Cell line: MEFs, HT-1080
Vildagliptin, alogliptin, linagliptin	Dipeptidyl-peptidase-4	Reduce lipid peroxidation via inhibiting DPP4	TP53-deficient CRC cells

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