Anlotinib Inhibits PFKFB3-Driven Glycolysis in Myofibroblasts to Reverse Pulmonary Fibrosis.
Anlotinib Inhibits PFKFB3-Driven Glycolysis in Myofibroblasts to Reverse Pulmonary Fibrosis.
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安罗替尼抑制肌成纤维细胞中 PFKFB3 驱动的糖酵解以逆转肺纤维化
DOI：
10.3389/fphar.2021.744826
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发表时间：
2021
影响因子：
5.6
通讯作者：
Dong H
中科院分区：
文献类型：
--
作者：
Chen W;Zhang J;Zhong W;Liu Y;Lu Y;Zeng Z;Huang H;Wan X;Meng X;Zou F;Cai S;Dong H
特发性肺纤维化（IPF）是一种致命的疾病，其中正常的肺泡网络逐渐被纤维化瘢痕取代。目前的证据表明，代谢改变与IPF中的肌成纤维细胞活化相关。已提出安洛替尼具有抗纤维化作用，但安洛替尼抗肺纤维化的疗效和机制尚未得到系统评价。在博来霉素诱导的小鼠模型和转化生长因子-β 1（TGF-β1）刺激的肺成纤维细胞中评价了安洛替尼的抗纤维化作用。我们测量了乳酸水平，2-NBDG葡萄糖摄取和细胞外酸化率（ECAR），以评估成纤维细胞中的糖酵解。RNA-蛋白质免疫共沉淀（RIP）和多核糖体分析，以探讨肺纤维化的糖酵解重编程的新机制。我们发现，安洛替尼减少了肌成纤维细胞的活化，并抑制了糖酵解的增加。此外，我们发现PCBP 3通过在成肌纤维细胞活化过程中促进其翻译而转录后增加PFKFB 3表达，从而促进成肌纤维细胞中的糖酵解。关于机制，安洛替尼通过下调PCBP 3、减少PFKFB 3翻译和抑制肌成纤维细胞中的糖酵解发挥有效的抗纤维化作用。此外，我们观察到安洛替尼对博来霉素诱导的肺纤维化具有预防和治疗抗纤维化作用。因此，我们将PCBP 3鉴定为参与糖酵解重编程和肺纤维化发生调节的蛋白质，并提出将其作为肺纤维化的治疗靶点。我们的数据表明，安洛替尼对肺具有抗纤维化作用，我们为这种作用提供了一种新的机制。安洛替尼可能成为治疗肺纤维化的一种新的有效候选药物。
Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the normal alveolar network is gradually replaced by fibrotic scars. Current evidence suggests that metabolic alterations correlate with myofibroblast activation in IPF. Anlotinib has been proposed to have antifibrotic effects, but the efficacy and mechanisms of anlotinib against lung fibrosis have not been systematically evaluated. The antifibrotic effects of anlotinib were evaluated in bleomycin-induced mouse models and transforming growth factor-beta 1 (TGF-β1)-stimulated lung fibroblasts. We measured lactate levels, 2-NBDG glucose uptake and the extracellular acidification rate (ECAR) to assess glycolysis in fibroblasts. RNA-protein coimmunoprecipitation (RIP) and polysome analyses were performed to investigate novel mechanisms of glycolytic reprogramming in pulmonary fibrosis. We found that anlotinib diminished myofibroblast activation and inhibited the augmentation of glycolysis. Moreover, we show that PCBP3 posttranscriptionally increases PFKFB3 expression by promoting its translation during myofibroblast activation, thus promoting glycolysis in myofibroblasts. Regarding mechanism, anlotinib exerts potent antifibrotic effects by downregulating PCBP3, reducing PFKFB3 translation and inhibiting glycolysis in myofibroblasts. Furthermore, we observed that anlotinib had preventative and therapeutic antifibrotic effects on bleomycin-induced pulmonary fibrosis. Therefore, we identify PCBP3 as a protein involved in the regulation of glycolysis reprogramming and lung fibrogenesis and propose it as a therapeutic target for pulmonary fibrosis. Our data suggest that anlotinib has antifibrotic effects on the lungs, and we provide a novel mechanism for this effect. Anlotinib may constitute a novel and potent candidate for the treatment of pulmonary fibrosis.
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DOI：
10.1165/rcmb.2013-0174oc
发表时间：
2014-01-01
影响因子：
6.4
作者：
Jarman, Elizabeth R.;Khambata, Valerie S.;Jarai, Gabor
通讯作者：
Jarai, Gabor
DOI：
10.1093/bioinformatics/btt495
发表时间：
2013-11-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Agostini F;Zanzoni A;Klus P;Marchese D;Cirillo D;Tartaglia GG
通讯作者：
Tartaglia GG
影响因子：
10
作者：
Cho, Soo Jung;Moon, Jong-Seok;Stout-Delgado, Heather
通讯作者：
Stout-Delgado, Heather
影响因子：
64.5
作者：
De Bock, Katrien;Georgiadou, Maria;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
6.9
作者：
Blaauboer, Marjolein E.;Boeijen, Fee R.;Everts, Vincent
通讯作者：
Everts, Vincent