清金散结方对中高危肺小结节患者SHOX2/RASSF1A/PTGER4 ctDNA甲基化影响的单臂研究
A single-arm study of the effects of
Qingjin Sanjie Formula on ctDNA methylation of SHOX2/RASSF1A/PTGER4 in patients with intermediate- to high-risk pulmonary small nodules- 北京中医药 2026年45卷第2期 页码：165-171
- 作者机构：
1.中国中医科学院望京医院呼吸科，北京 100102
2.中国中医科学院望京医院放射科，北京 100102
3.黑龙江中医药大学第一临床医学院，哈尔滨 150040
4.中国中医科学院望京医院病理科，北京 100102
- 作者简介：
曹仁爽，男，28岁，博士研究生，住院医师。研究方向：中医药防治慢性肺系疾病。
高峰，E-mail：wjyyhxk@163.com
- 基金信息：中国中医科学院望京医院高水平中医医院建设项目——中医药临床循证研究重点项目(WJYY-XZKT-2023-11)
DOI：10.16025/j.1674-1307.2026.02.004
中图分类号：收稿：2025-01-07，
纸质出版：2026-02-25
- 稿件说明：
移动端阅览
曹仁爽，王彬，来薛，等.清金散结方对中高危肺小结节患者SHOX2/RASSF1A/PTGER4 ctDNA甲基化影响的单臂研究［J］.北京中医药，2026，45（2）：165-171.
CAO Renshuang,WANG Bin,LAI Xue,et al.A single-arm study of the effects of Qingjin Sanjie Formula on ctDNA methylation of SHOX2/RASSF1A/PTGER4 in patients with intermediate- to high-risk pulmonary small nodules[J]. Beijing Journal of Traditional Chinese Medicine,2026,45(02):165-171.
曹仁爽，王彬，来薛，等.清金散结方对中高危肺小结节患者SHOX2/RASSF1A/PTGER4 ctDNA甲基化影响的单臂研究［J］.北京中医药，2026，45（2）：165-171. DOI： 10.16025/j.1674-1307.2026.02.004.
CAO Renshuang,WANG Bin,LAI Xue,et al.A single-arm study of the effects of Qingjin Sanjie Formula on ctDNA methylation of SHOX2/RASSF1A/PTGER4 in patients with intermediate- to high-risk pulmonary small nodules[J]. Beijing Journal of Traditional Chinese Medicine,2026,45(02):165-171. DOI： 10.16025/j.1674-1307.2026.02.004.
摘要
目的
2
探讨清金散结方对中高危肺小结节患者外周血循环肿瘤DNA（ctDNA）中短臂同源盒基因2（SHOX2）、Ras相关结构域家族1亚型A（RASSF1A）、前列腺素E受体4（PTGER4）基因甲基化水平的影响，评估其在肺癌早期表观遗传调控中的潜在作用。
方法
2
采用生物信息学分析方法，基于TCGA数据库中肺腺癌的甲基化与表达数据，筛选与肺癌相关的差异甲基化区域（DMR）；同时开展一项前瞻性、单臂临床观察性研究，纳入23例符合标准的中高危肺小结节患者，给予清金散结方水煎剂口服，2次/d，持续12周。治疗前后采集患者外周血，检测ctDNA中SHOX2、RASSF1A、PTGER4基因的特定位点甲基化水平，并记录结节影像学特征及中医体质评分。
结果
2
生物信息学分析显示，SHOX2启动子区域在肺癌组织中呈高甲基化状态，且与其基因表达呈正相关；RASSF1A与PTGER4基因启动子区域的高甲基化与其表达沉默相关。临床研究结果显示，清金散结方干预12周后，患者ctDNA中SHOX2、RASSF1A、PTGER4的甲基化水平较基线显著下降（
P
<
0.05），且甲基化水平与肺结节最大直径呈正相关。然而，中医体质评分及结节最大直径在治疗前后未见显著变化（
P
>
0.05）。亚组分析提示，女性和非吸烟者在甲基化水平改善方面更为明显。
结论
2
SHOX2、RASSF1A、PTGER4基因的甲基化状态与肺癌风险密切相关。清金散结方可显著降低中高危肺小结节患者上述基因的ctDNA甲基化水平，提示其可能通过调控表观遗传机制，发挥干预中高危肺小结节的作用。
Abstract
Objective
2
To investigate the effects of
Qingjin Sanjie Formula
on the methylation levels of short stature homeobox 2 （SHOX2）， Ras association domain family 1 isoform A （RASSF1A）， and prostaglandin E receptor 4 （PTGER4） genes in circulating tumor DNA （ctDNA） from peripheral blood of patients with intermediate- to high-risk pulmonary small nodules （PSNs）， and to evaluate its potential role in early epigenetic regulation of lung cancer.
Methods
2
Bioinformatics analysis was performed based on methylation and gene expression data of lung adenocarcinoma from The Cancer Genome Atlas （TCGA） database to identify differentially methylated regions （DMRs） associated with lung cancer. Meanwhile， a prospective， single-arm clinical observational study was conducted， enrolling 23 patients with intermediate- to high-risk PSNs who met the inclusion criteria. Patients received
Qingjin Sanjie Formula
decoction orally， twice daily， for 12 weeks. Peripheral blood samples were collected before and after treatment to assess site-specific methylation levels of SHOX2， RASSF1A， and PTGER4 genes in ctDNA. Nodule imaging characteristics and traditional Chinese medicine （TCM） constitution scores were also recorded.
Results
2
Bioinformatics analysis showed that the promoter region of SHOX2 was hypermethylated in lung cancer tissues and positively correlated with its gene expression， whereas hypermethylation of the promoter regions of RASSF1A and PTGER4 was associated with gene silencing. Clinical results demonstrated that after 12 weeks of intervention with
Qingjin Sanjie Formula
， methylation levels of SHOX2， RASSF1A， and PTGER4 in ctDNA were significantly reduced compared with baseline （
P
<
0.05）， and the methylation levels were positively correlated with the maximum diameter of pulmonary nodules. However， no sign
ificant changes were observed in TCM constitution scores or maximum nodule diameter before and after treatment （
P
>
0.05）. Subgroup analysis suggested that improvements in methylation levels were more pronounced in female patients and non-smokers.
Conclusion
2
The methylation status of SHOX2， RASSF1A， and PTGER4 genes is closely associated with lung cancer risk.
Qingjin Sanjie Formula
can significantly reduce ctDNA methylation levels of these genes in patients with intermediate- to high-risk PSNs， suggesting that it may exert therapeutic effects by modulating epigenetic mechanisms.
关键词
Keywords
references
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