酪氨酸激酶抑制剂奈拉替尼通过靶向激活的肝星状细胞来减轻肝纤维化。

Tyrosine kinase inhibitor neratinib attenuates liver fibrosis by targeting activated hepatic stellate cells.

机构信息

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Center for Nanomedicine At the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

出版信息

Sci Rep. 2020 Sep 8;10(1):14756. doi: 10.1038/s41598-020-71688-2.

DOI:10.1038/s41598-020-71688-2

PMID:32901093

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7479613/

Abstract

Liver fibrosis, a common outcome of chronic liver disease characterized by excessive accumulation of extracellular matrix (ECM), is a leading cause of mortality worldwide. The tyrosine kinase inhibitor neratinib is a human epidermal growth factor receptor 2 (HER2) inhibitor approved by the FDA for HER2-positive breast cancer treatment; however, it has not yet been evaluated for liver fibrosis treatment. We elucidated the anti-fibrotic effects of neratinib in hepatic stellate cells (HSCs) and in vivo models of CCl-induced liver fibrosis. HSC activation is a key step in liver fibrogenesis and has a crucial role in collagen deposition, as it is primarily responsible for excessive ECM production. The effect of neratinib on HSC was evaluated in transforming growth factor (TGF-β)-incubated LX-2 cells and culture-activated primary human HSCs. In vivo study results indicated that neratinib inhibited the inflammatory response, HSC differentiation, and collagen accumulation induced by CCl. Moreover, the anti-fibrotic effects of neratinib were not associated with the HER2 signaling pathways. Neratinib inhibited FGF2 expression in activated HSCs and serum FGF2 level in the model, suggesting that neratinib possessed therapeutic potency against liver fibrosis and the potential for application against other fibrotic diseases.

摘要

肝纤维化是一种常见的慢性肝病后果，其特征是细胞外基质（ECM）过度积累，是全球死亡的主要原因。酪氨酸激酶抑制剂奈拉替尼是一种人表皮生长因子受体 2（HER2）抑制剂，已被 FDA 批准用于治疗 HER2 阳性乳腺癌；然而，它尚未被评估用于治疗肝纤维化。我们研究了奈拉替尼在肝星状细胞（HSCs）和 CCl 诱导的肝纤维化体内模型中的抗纤维化作用。HSC 激活是肝纤维化发生的关键步骤，在胶原沉积中起着至关重要的作用，因为它主要负责 ECM 的过度产生。我们在转化生长因子（TGF-β）孵育的 LX-2 细胞和培养激活的原代人 HSCs 中评估了奈拉替尼对 HSC 的作用。体内研究结果表明，奈拉替尼抑制了 CCl 诱导的炎症反应、HSC 分化和胶原积累。此外，奈拉替尼的抗纤维化作用与 HER2 信号通路无关。奈拉替尼抑制了激活的 HSCs 中的 FGF2 表达和模型中的血清 FGF2 水平，表明奈拉替尼具有治疗肝纤维化的潜力，并有可能应用于其他纤维化疾病。