Bai Mouqi, Liang Gege, Sun Ruijie, Dong Yuyu, Geng Cuicui, Wang Bin, Liu Baogang, Sun Lizhe
The Second Clinical Medical School, Shaanxi University of Chinese Medicine, Xianyang, 712046, Shaanxi, China.
Oncology Department of The Second Affiliated Hospital, Shaanxi University of Chinese Medicine, Xianyang, 712000, Shaanxi, China.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 16. doi: 10.1007/s00210-025-04361-y.
Radiation-induced lung injury (RILI), manifesting in its initial phase as radiation pneumonitis (RP) and progressing over time to radiation-induced pulmonary fibrosis (RIPF), represents a significant adverse consequence associated with thoracic radiation therapy. Currently, there are limited therapeutic options for RILI. Anlotinib was confirmed the efficacy of pulmonary fibrosis. Therefore, anlotinib has the potential to treat RILI. To investigate the therapeutic role of anlotinib in RILI. RILI model in mice was successfully developed for evaluating the therapeutic efficacy of anlotinib. We used network pharmacology to find six target genes and analysed the correlation between these genes and RILI-related cytokines. Molecular docking further validates the binding ability of these target genes and anlotinib. We found the importance of TGF-β in anlotinib treatment of RILI by the results of network pharmacology and correlation analysis. We then used immunohistochemistry to demonstrate that anlotinib treats RILI by lowering TGF-β. Through enrichment analysis, we obtained potential therapeutic pathways and validated them with WB. In vivo investigations demonstrated that anlotinib is able to treat RILI: Inflammation, fibrosis, and apoptosis are reduced. This result is likely to be related to the reduction of TGF-β: The therapeutic mechanism potentially involves six genes, namely, FLT1, AKT1, KDR, TGFB2, PDGFRB1, and FGFR1; these targets bind well to anlotinib; we found that the expression of most of cytokines affecting the particular processes of RILI was closely associated with the six genes, in particular TGF-β1-3; immunohistochemistry further demonstrates that anlotinib treats RILI by lowering TGF-β1-3. In addition, KEGG enrichment analysis reveals possible pathways involving in therapeutic effects, including the PI3K-Akt, MAPK, Rap1, and Ras pathway. WB showed that anlotinib treatment significantly inhibited the PI3K/Akt signalling pathway. Therefore, anlotinib has the potential for treating RILI. Our results indicated the potential targets and molecular mechanism of anlotinib against RILI.
放射性肺损伤（RILI），在其初始阶段表现为放射性肺炎（RP），并随时间进展为放射性肺纤维化（RIPF），是胸部放射治疗的一个重要不良后果。目前，RILI的治疗选择有限。安罗替尼已被证实对肺纤维化有效。因此，安罗替尼有治疗RILI的潜力。为了研究安罗替尼在RILI中的治疗作用。成功建立了小鼠RILI模型以评估安罗替尼的治疗效果。我们使用网络药理学找到六个靶基因，并分析了这些基因与RILI相关细胞因子之间的相关性。分子对接进一步验证了这些靶基因与安罗替尼的结合能力。通过网络药理学和相关性分析的结果，我们发现了转化生长因子-β（TGF-β）在安罗替尼治疗RILI中的重要性。然后我们使用免疫组织化学证明安罗替尼通过降低TGF-β来治疗RILI。通过富集分析，我们获得了潜在的治疗途径并用蛋白质免疫印迹法（WB）进行了验证。体内研究表明安罗替尼能够治疗RILI：炎症、纤维化和细胞凋亡减少。这一结果可能与TGF-β的降低有关：治疗机制可能涉及六个基因，即血管内皮生长因子受体1（FLT1）、蛋白激酶B1（AKT1）、血管内皮生长因子受体2（KDR）、转化生长因子-β2（TGFB2）、血小板衍生生长因子受体β1（PDGFRB1）和成纤维细胞生长因子受体1（FGFR1）；这些靶点与安罗替尼结合良好；我们发现影响RILI特定过程的大多数细胞因子的表达与这六个基因密切相关，特别是TGF-β1-3；免疫组织化学进一步证明安罗替尼通过降低TGF-β1-3来治疗RILI。此外，京都基因与基因组百科全书（KEGG）富集分析揭示了可能参与治疗作用的途径，包括磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）、丝裂原活化蛋白激酶（MAPK）、Rap1和Ras途径。WB显示安罗替尼治疗显著抑制PI3K/Akt信号通路。因此，安罗替尼有治疗RILI的潜力。我们的结果表明了安罗替尼抗RILI的潜在靶点和分子机制。
