Danshensu methyl ester enhances autophagy to attenuate pulmonary fibrosis by targeting lncIAPF-HuR complex.
Danshensu methyl ester enhances autophagy to attenuate pulmonary fibrosis by targeting lncIAPF-HuR complex.
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DOI：
10.3389/fphar.2022.1013098
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
肺纤维化是一种不可逆的纤维化过程，具有高死亡率和有限的治疗选择;因此，开发新型治疗药物至关重要。本研究合成了丹参素甲酯（DME），并研究了其对TGF-β1刺激的肺成纤维细胞和博来霉素诱导的肺纤维化的抑制作用。结果显示，DME在体内和体外降低分化相关蛋白的表达，包括成纤维细胞活化蛋白1（FAP 1）和S100钙结合蛋白A4（S100 A4），以及纤维化标志物，如α-SMA、波形蛋白和胶原。此外，DME显着抑制肌成纤维细胞增殖和迁移。染色质免疫沉淀-PCR、RNA免疫沉淀、半衰期和其他实验表明，DME通过TGF-β1信号转导抑制转录激活因子3的表达，导致lncIAPF转录和稳定性降低。DME通过下调lncIAPF抑制人抗原R（HuR）核质转位，促进其降解，从而显著降低HuR靶基因如负性自噬调节因子（EZH 2、STAT 1和FOXK 1）的表达。总的来说，我们的结果表明，DME通过下调lncIAPF-HuR介导的自噬轴来增强自噬以减轻肺纤维化，并且lncIAPF-HuR复合物可以是药物作用的靶点。
Pulmonary fibrosis is an irreversible fibrotic process that has a high mortality rate and limited treatment options; thus, developing a novel therapeutic drug is critical. In this study, we synthesized danshensu methyl ester (DME) and explored its anti-pulmonary fibrotic ability on TGF-β1-stimulated lung fibroblast in vitro and on bleomycin-induced pulmonary fibrosis in vivo. Results showed that DME decreased the expression of differentiation-related proteins, including fibroblast activation protein 1 (FAP1) and S100 calcium-binding protein A4 (S100A4), and fibrotic markers, such as a-SMA, vimentin, and collagen in vivo and in vitro. In addition, DME markedly repressed myofibroblast proliferation and migration. Mechanistically, chromatin immunoprecipitation–PCR, RNA immunoprecipitation, half-life, and other experiments revealed that DME inhibited activating transcription factor 3 expression via TGF-β1 signal transduction leading to a decrease in lncIAPF transcription and stability. Moreover, DME blocked human antigen R (HuR) nucleocytoplasmic translocation and promoted its degradation via downregulating lncIAPF, which markedly decreased the expression of HuR target genes such as negative autophagic regulators (EZH2, STAT1, and FOXK1). Collectively, our results demonstrated that DME enhanced autophagy to attenuate pulmonary fibrosis via downregulating the lncIAPF–HuR-mediated autophagic axis and the lncIAPF–HuR complex can be the target for drug action.
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