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BACKGROUND

Radiation-induced lung injury (RILI) is a severe side effect of radiotherapy for non-small cell lung cancer (NSCLC) ,and one of the major hindrances to improve the efficacy of radiotherapy. Previous studies have confirmed that sodium butyrate (NaB) has potential of anti-radiation toxicity. However, the mechanism of the protective effect of NaB against RILI has not yet been clarified. This study aimed to explore the underlying protective mechanisms of NaB against RILI in NSCLC through network pharmacology, molecular docking, molecular dynamic simulations and experiments.

METHODS

The predictive target genes of NaB were obtained from the PharmMapper database and the literature review. The involved genes of RILI and NSCLC were predicted using OMIM and GeneCards database. The intersectional genes of drug and disease were identified using the Venny tool and uploaded to the Cytoscape software to identify 5 core target genes of NaB associated with RILI. The correlations between the 5 core target genes and EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors were analyzed using TIMER 2.0, TIMER and TISIDB databases. We constructed the mechanism maps of the 3 key signaling pathways using the KEGG database based on the results of GO and KEGG analyses from Metascape database. The 5 core target genes and drug were docked using the AutoDock Vina tool and visualized using PyMOL software. GROMACS software was used to perform 100 ns molecular dynamics simulation. Irradiation-induced lung injury model in mice were established to assess the therapeutic effects of NaB.

RESULTS

A total of 51 intersectional genes involved in NaB against RILI in NSCLC were identified. The 5 core target genes were AKT1, TP53, NOTCH1, SIRT1, and PTEN. The expressions of the 5 core target genes were significantly associated with EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors, respectively. The results from GO analysis of the 51 intersectional genes revealed that the biological processes were focused on the regulation of smooth muscle cell proliferation, oxidative stress and cell death, while the three key KEGG pathways were enriched in PI3K-Akt signal pathway, p53 signal pathway, and FOXO signal pathway. The docking of NaB with the 5 core target genes showed affinity and stability, especially AKT1. experiments showed that NaB treatment significantly protected mice from RILI, with reduced lung histological damage. In addition, NaB treatment significantly inhibited the PI3K/Akt signaling pathway.

CONCLUSIONS

NaB may protect patients from RILI in NSCLC through multiple target genes including AKT1, TP53, NOTCH1, SIRT1 and PTEN, with multiple signaling pathways involving, including PI3K-Akt pathway, p53 pathway, and FOXO pathways. Our findings effectively provide a feasible theoretical basis to further elucidate the mechanism of NaB in the treatment of RILI.

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

背景

放射性肺损伤（RILI）是非小细胞肺癌（NSCLC）放疗的严重副作用，也是提高放疗疗效的主要障碍之一。既往研究证实丁酸钠（NaB）具有抗辐射毒性的潜力。然而，NaB对RILI的保护作用机制尚未阐明。本研究旨在通过网络药理学、分子对接、分子动力学模拟和实验，探索NaB对NSCLC中RILI的潜在保护机制。

方法

从PharmMapper数据库和文献综述中获取NaB的预测靶基因。使用OMIM和GeneCards数据库预测RILI和NSCLC的相关基因。使用Venny工具鉴定药物和疾病的交集基因，并上传到Cytoscape软件中，以鉴定与RILI相关的NaB的5个核心靶基因。使用TIMER 2.0、TIMER和TISIDB数据库分析这5个核心靶基因与表皮生长因子受体（EGFR）、程序性死亡受体1配体（PD-L1）、免疫浸润、趋化因子和趋化因子受体之间的相关性。基于Metascape数据库的基因本体（GO）和京都基因与基因组百科全书（KEGG）分析结果，使用KEGG数据库构建3条关键信号通路的机制图。使用AutoDock Vina工具对5个核心靶基因和药物进行对接，并使用PyMOL软件进行可视化。使用GROMACS软件进行100纳秒的分子动力学模拟。建立小鼠放射性肺损伤模型以评估NaB的治疗效果。

结果

共鉴定出51个参与NaB对NSCLC中RILI作用的交集基因。5个核心靶基因为蛋白激酶B1（AKT1）、肿瘤蛋白p53（TP53）、神经氨酸酶1（NOTCH1）、沉默信息调节因子1（SIRT1）和第10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN）。这5个核心靶基因的表达分别与EGFR、PD-L1、免疫浸润、趋化因子和趋化因子受体显著相关。对51个交集基因的GO分析结果显示，生物学过程主要集中在平滑肌细胞增殖、氧化应激和细胞死亡的调节，而3条关键的KEGG通路在磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）信号通路、p53信号通路和叉头框蛋白O（FOXO）信号通路中富集。NaB与5个核心靶基因的对接显示出亲和力和稳定性，尤其是与AKT1。实验表明，NaB治疗可显著保护小鼠免受RILI，减轻肺组织学损伤。此外，NaB治疗显著抑制PI3K/Akt信号通路。