Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells but exacerbates chronic liver injury.
Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells but exacerbates chronic liver injury.
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DOI：
10.1111/liv.14945
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Diehl AM
中科院分区：
文献类型：
--
作者：
Du K;Oh SH;Dutta RK;Sun T;Yang WH;Chi JT;Diehl AM
肝损伤的结果是由控制肌成纤维细胞（活化的）肝星状细胞（mf - hsc）积聚的因素决定的，但特异性阻断这一过程的治疗方法尚未发现。我们评估了通过抑制半胱氨酸/谷氨酸反转运蛋白xCT可以安全地减少造血干细胞和肝纤维化的假设。在HSC系和原代小鼠HSC中破坏xCT活性，以确定其对HSC生物学的影响。为了进行比较，我们还测定了xCT在小鼠原代肝细胞中的表达和功能。最后，在小鼠肝纤维化模型中评估xCT的作用。我们发现，小鼠原代造血干细胞中的xCT mRNA水平几乎比小鼠原代肝细胞高1倍。此外，原代小鼠HSC在成为MF时显著诱导xCT，抑制xCT可阻断GSH合成，降低生长和纤维化基因表达，引发HSC铁凋亡。xCT抑制剂在体外诱导hsc大量铁凋亡对肝细胞活力没有影响，xCT抑制剂在急性肝损伤小鼠中减少肝纤维化而不加重肝损伤。然而，TGFβ处理上调xCT并引发培养的原代小鼠肝细胞铁凋亡。在慢性肝损伤期间，xCT抑制剂加重了损伤，损害了再生，并未能改善纤维化，证实了hsc和肝细胞在慢性氧化应激中生存的机制相似。抑制xCT可抑制肌成纤维细胞活性，诱导造血干细胞铁下垂。然而，靶向xCT抑制mf - hsc将有必要利用铁下垂作为一种抗纤维化策略。
The outcome of liver injury is dictated by factors that control accumulation of myofibroblastic (activated) hepatic stellate cells (MF-HSCs) but therapies that specifically block this process have not been discovered. We evaluated the hypothesis that MF-HSCs and liver fibrosis could be safely reduced by inhibiting the cysteine/glutamate antiporter xCT. xCT activity was disrupted in both HSC lines and primary mouse HSCs to determine its effect on HSC biology. For comparison, xCT expression and function were also determined in primary mouse hepatocytes. Finally, the roles of xCT were assessed in mouse models of liver fibrosis. We found that xCT mRNA levels were almost a log-fold higher in primary mouse HSCs than in primary mouse hepatocytes. Further, primary mouse HSCs dramatically induced xCT as they became MF, and inhibiting xCT blocked GSH synthesis, reduced growth and fibrogenic gene expression and triggered HSC ferroptosis. Doses of xCT inhibitors that induced massive ferroptosis in HSCs had no effect on hepatocyte viability in vitro, and xCT inhibitors reduced liver fibrosis without worsening liver injury in mice with acute liver injury. However, TGFβ treatment up-regulated xCT and triggered ferroptosis in cultured primary mouse hepatocytes. During chronic liver injury, xCT inhibitors exacerbated injury, impaired regeneration and failed to improve fibrosis, confirming that HSCs and hepatocytes deploy similar mechanisms to survive chronic oxidative stress. Inhibiting xCT can suppress myofibroblastic activity and induce ferroptosis of MF-HSCs. However, targeting xCT inhibition to MF-HSCs will be necessary to exploit ferroptosis as an anti-fibrotic strategy.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
p62-Keap1-NRF2 通路的激活可防止肝细胞癌细胞中的铁死亡。
DOI：
10.1002/hep.28251
发表时间：
2016-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Sun X;Ou Z;Chen R;Niu X;Chen D;Kang R;Tang D
通讯作者：
Tang D
影响因子：
29.4
作者：
Angulo P;Kleiner DE;Dam-Larsen S;Adams LA;Bjornsson ES;Charatcharoenwitthaya P;Mills PR;Keach JC;Lafferty HD;Stahler A;Haflidadottir S;Bendtsen F
通讯作者：
Bendtsen F
DOI：
10.1186/s40880-018-0288-x
发表时间：
2018-04-25
期刊：
Cancer communications (London, England)
影响因子：
--
作者：
Koppula P;Zhang Y;Zhuang L;Gan B
通讯作者：
Gan B
影响因子：
4.8
作者：
Davis, BH;Chen, AP;Beno, DWA
通讯作者：
Beno, DWA