目的 基于“诸气膹郁，皆属于肺”理论，通过孟德尔随机化（Mendelian randomization，MR）分析探讨肺腺癌（lung adenocarcinoma，LUAD）与重度抑郁症（major depressive disorder，MDD）的遗传因果关系，并预测干预LUAD相关性抑郁（lung adenocarcinoma-related depression，LAD）的潜在中药。方法 从IEU OpenGWAS数据库获取LUAD与MDD的全基因组关联研究（genome-wide association studies，GWAS）数据集，主要通过R软件的TwoSampleMR包进行MR分析和结果的稳健性评估。通过Ensembl数据库预测工具变量的邻近基因（instrumental variable nearby genes，IVNGs），基于IVNGs进行功能富集分析并分别通过CTD数据库和ITCM数据库预测相关的化学成分和潜在的干预中药。应用古今医案云平台（V2.3.9）对中药进行统计分析，以探讨其治疗疾病的理法方药。结果 MR分析的逆方差加权（inverse variance weighted，IVW）方法结果（β＝0.002 05，P＝0.018 99）提示LUAD与MDD发生存在弱正向因果效应，稳健性分析未发现显著的异质性和水平多效性，结果可靠。富集分析结果显示主要与胆碱能信号通路有关。聚类分析结果显示频次在前30的中药可大致分为5大类。所有潜在干预中药的四气以温为主，平、寒次之；五味以甘为主，苦、辛次之；归经以肝为主，肺、脾、胃、肾和心次之；功效主要以清热解毒为主，凉血止血、解毒、止血及清热利湿次之。对频次前15的中药进行经典名方识别，结果显示主要是通过麻黄、栀子、薏苡仁、蒲公英和肉苁蓉5味中药识别，相似的经典名方有麻黄类方、槐花散、黄连解毒汤、苇茎汤、五味消毒饮、济川煎、化肝煎和桑杏汤等。结论 基于“诸气膹郁，皆属于肺”理论，发现LUAD与MDD存在弱正向遗传因果效应，LUAD可能通过影响神经信号传递及神经调控机制，尤其是胆碱能信号通路促进MDD的发生。结合中医“态靶”医学理论和中药预测结果探析了中医治疗LAD的理法方药，旨在为LAD患者的中医药治疗提供参考，以改善LUAD患者的整体治疗效果及心理健康。

Objective To explore the genetic causal relationship between lung adenocarcinoma (LUAD) and major depressive disorder (MDD) through Mendelian randomization (MR) analysis, based on the theory of “all qi stagnation and depression related to lung ”, and predict potential traditional Chinese medicines for the intervention of lung adenocarcinoma-related depression (LAD). Methods Genome-wide association studies (GWAS) datasets for LUAD and MDD were obtained from the IEU OpenGWAS database. MR analysis and robustness assessment were primarily conducted using the TwoSampleMR package in R software. Instrumental variable nearby genes (IVNGs) were predicted using the Ensembl database. Functional enrichment analysis was performed based on IVNGs, and the CTD and ITCM databases were used to predict relevant chemical components and potential traditional Chinese medicine (TCM) interventions. The Classical and Modern Medical Cases Cloud Platform (V2.3.9) was used for statistical analysis of TCM, focusing on the therapeutic principles and prescriptions. Results MR analysis using inverse variance weighted (IVW) method (β = 0.002 05, P = 0.018 99) suggested a weak positive causal effect between LUAD and MDD. Robustness analysis showed no significant heterogeneity or horizontal pleiotropy, confirming the reliability of the results. Enrichment analysis revealed a significant association with the cholinergic synaptic signaling pathway. Clustering analysis categorized the top 30 most frequent TCM into five main groups. The four qi (temperature properties) of all potential TCM interventions were predominantly warm, followed by neutral and cold; The five flavors were primarily sweet, with bitter and pungent flavors following. The meridians were mainly attributed to the liver, followed by the lung, spleen, stomach, kidney, and heart. The primary therapeutic effects focused on clearing heat and detoxifying, cooling blood and stopping bleeding, detoxifying, and clearing heat and dampness. Classical prescriptions corresponding to the top 15 frequent TCM included Mahuang (Ephedrae Herba), Zhizi (Gardeniae Fructus), Yiyiren (Coicis Semen), Pugongying (Taraxaci Herba), and Roucongrong (Cistanches Herba), with similar classical prescriptions being Mahuang-based formulas, Huaihua Powder (槐花散), Huanglian Jiedu Decoction (黄连解毒汤), Weijing Decoction (苇茎汤), Wuwei Xiaodu Drink (五味消毒饮), Jichuan Decoction (济川煎), Huagan Decoction (化肝煎), and Sangxing Decoction (桑杏汤). Conclusion Based on the theory “all qi stagnation and depression related to lung ”, a weak positive genetic causal effect between LUAD and MDD was found. LUAD may promote the development of MDD by influencing neural signaling transmission and regulatory mechanisms, particularly through the cholinergic pathway. Additionally, combining the “Target-Status” medical theory and the predicted TCM results, this study explored potential TCM treatments for LAD, aiming to provide references for the TCM treatment of LAD patients to improve the overall therapeutic outcomes and mental health of LUAD patients.

Q811.4;R285

国家自然科学基金项目（82074425）;湖南省自然科学基金项目（2023JJ30448）;长沙市自然科学基金项目（kq2202264）;湖南省重点研发计划（2021SK2006，2022SK2018，2022SK2124，2023SK2057）;湖南省健康研究项目（20232605）;湖南省高层次人才重大科研专项（R2023081）;湖南省卫健委中医药神农领军人才项目[湘中医药(2021)10号];湖南省科技拔尖领军人才项目（2022RC3081）;湖南省中医药管理局“十四五”中医药科技创新平台建设项目[湘中医药函（2022）93号];湖南省科技创新人才项目;国家重大疑难疾病（癌症治疗后慢性疼痛）中西医临床协作项目;中医药特色安宁疗护服务模式和中医药安宁疗护技术研究（ZXYJHMZYYS2024-034）