Xiao Ting, Gao Dandi, Gu Xiaoting, Zhang Yanping, Zhu Yuxin, Zhang Zihui, He Yiming, Wei Luqing, Li Hongli, Zhou Honggang, Yang Cheng
State Key Laboratory of Medicinal Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China.
State Key Laboratory of Medicinal Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China.
Eur J Pharmacol. 2023 Nov 5;958:175981. doi: 10.1016/j.ejphar.2023.175981. Epub 2023 Aug 12.
Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease characterized by myofibroblast proliferation and extracellular matrix deposition that has a high mortality rate and limited therapeutic options. Flavokawain A(FKA) is the major component of chalcone in kava extract. FKA has been reported to inhibit TGF-β1-induced cardiomyocyte fibrosis by suppressing ROS production in A7r5 cells, but the role and mechanism of FKA in pulmonary fibrosis are unknown. In this study, we evaluated the effect of FKA on pulmonary fibrosis using an animal model of bleomycin-induced pulmonary fibrosis and showed that FKA alleviated the development of pulmonary fibrosis in a dose-dependent manner and improved lung function as well as collagen deposition and extracellular matrix accumulation in mice. In vitro studies showed that FKA inhibited myofibroblast activation and lung fibrosis progression by inhibiting TGF-β1/Smad signaling in a dose-dependent manner. In addition, we identified CXCL12 as a potential target of FKA through target prediction. Molecular docking, CETSA(cellular thermal displacement assay) and silver staining assays further demonstrated that FKA could interact with CXCL12 and that FKA could inhibit CXCL12 dimerization in vitro. Further analysis revealed that FKA could inhibit fibroblast activation and reduce extracellular matrix (ECM) production and collagen deposition by blocking CXCL12/CXCR4 signaling, and knocking down CXCR4 expression could weaken the inhibitory effect of FKA on CXCL12/CXCR4 signal transduction. In conclusion, our study showed that FKA inhibited CXCL12/CXCR4 signaling by inhibiting CXCL12 dimerization, blocked the CXCL12/CXCR4 signaling pathway and inhibited the TGF-β1-mediated signaling pathway to ameliorate pulmonary fibrosis, and FKA is a promising therapeutic agent for pulmonary fibrosis.
特发性肺纤维化是一种进行性纤维化性肺病，其特征为肌成纤维细胞增殖和细胞外基质沉积，死亡率高且治疗选择有限。黄酮卡瓦因A（FKA）是卡瓦提取物中查耳酮的主要成分。据报道，FKA通过抑制A7r5细胞中的活性氧生成来抑制转化生长因子-β1（TGF-β1）诱导的心肌细胞纤维化，但FKA在肺纤维化中的作用和机制尚不清楚。在本研究中，我们使用博来霉素诱导的肺纤维化动物模型评估了FKA对肺纤维化的影响，结果表明FKA以剂量依赖性方式减轻了肺纤维化的发展，并改善了小鼠的肺功能以及胶原沉积和细胞外基质积聚。体外研究表明，FKA通过以剂量依赖性方式抑制TGF-β1/ Smad信号传导来抑制肌成纤维细胞活化和肺纤维化进展。此外，我们通过靶点预测确定CXCL12为FKA的潜在靶点。分子对接、细胞热位移分析（CETSA）和银染分析进一步证明FKA可与CXCL12相互作用，并且FKA可在体外抑制CXCL12二聚化。进一步分析表明，FKA可通过阻断CXCL12/ CXCR4信号传导来抑制成纤维细胞活化并减少细胞外基质（ECM）产生和胶原沉积，敲低CXCR4表达可减弱FKA对CXCL12/ CXCR4信号转导的抑制作用。总之，我们的研究表明，FKA通过抑制CXCL12二聚化来抑制CXCL12/ CXCR4信号传导，阻断CXCL12/ CXCR4信号通路并抑制TGF-β1介导的信号通路以改善肺纤维化，并且FKA是一种有前途的肺纤维化治疗药物。
