Lung cancer is a leading cause of morbidity and mortality, making its prevention and treatment a key focus of research. Circadian rhythm disruption (CRD) is considered an important risk factor for lung cancer, but the causal relationship between CRD and lung cancer remains unclear.

To investigate the causal relationship and potential mechanisms between circadian rhythm disruption and lung cancer risk, and to predict potential Traditional Chinese Medicine (TCM) interventions.

GWAS data on daytime napping, daytime sleepiness, short and long sleep duration, chronotype, insomnia, and early waking were obtained from UK Biobank and other sources, while lung cancer-related data, including overall lung cancer, lung adenocarcinoma (LUAD) , lung squamous cell carcinoma (LUSC) , and small cell lung cancer (SCLC) , were collected from the IEU Open GWAS database. Mendelian randomization (MR) analysis was conducted using the inverse-variance weighted (IVW) method to evaluate the causal relationship between circadian rhythm disruption and lung cancer, with supplementary methods used to confirm result robustness. Core genes were identified through SNPs localization and PPI network analysis, followed by functional enrichment and survival analysis. Core genes were then uploaded to the Coremine database to identify TCMs with potential intervention effects. The properties, flavors, meridian tropism, and efficacy of the TCMs were cataloged. Core TCMs were then selected, and their key components were obtained from the TCMSP and BATMAN-TCM databases. Molecular docking was used to validate the binding ability of the key components of the core TCMs to the core genes.

Insomnia (OR=1.149, 95%CI=1.074-1.232, P=0.013) and short sleep duration (OR=1.462, 95%CI=1.033-2.061, P=0.031) showed a causal relationship with lung cancer. Insomnia (OR=1.181, 95%CI=1.061-1.322, P=0.001) , short sleep duration (OR=1.563, 95%CI=1.024-2.401, P=0.038) , and daytime sleepiness (OR=4.033, 95%CI=1.062-15.434, P=0.042) were causally linked to LUAD, while insomnia (OR=1.152, 95%CI=1.028-1.281, P=0.001) was linked to LUSC and short sleep duration (OR=1.952, 95%CI=1.120-3.383, P=0.017) to SCLC. A total of 139 core genes were identified, enriched in pathways such as GPCR, MAPK, and PI3K/Akt. The top five core genes included EP300, GAPDH, GNB1, GNG13, and TNF. EP300 expression correlated positively with survival in LUAD, LUSC, and SCLC patients (P<0.05) . GNB1 expression negatively correlated with survival in LUAD patients but positively with survival in SCLC patients (P<0.05) . GAPDH, GNG13, and TNF expressions negatively correlated with survival in LUAD patients (P<0.05) . Forty TCMs, including Shui Niu Jiao, Dan Shen, Yu Nao Shi, Huang Qin, Yu Jin, Huang Qi, Ling Zhi, and Ren Shen were predicted and screened, with sweet flavor being predominant, followed by bitter and pungent, and cold nature being dominant, followed by warm and neutral. The TCMs mainly targeted the liver, spleen, lungs, stomach, heart, and kidney meridians, with functions focused on tonifying qi, promoting blood circulation, and clearing heat and toxins. Eight key herbs (Shui Niu Jiao, Dan Shen, San Qi, Huang Qin, Yu Jin, Jiang Huang, Yu Mi Xu, Ling Zhi) showed excellent molecular docking affinity (binding energy<-4 kcal/mol) with core target genes.

The findings suggest a causal relationship between circadian rhythm disruption and lung cancer, with potential mechanisms involving pathways such as GPCR, MAPK, and PI3K/Akt. The predicted TCMs offer new insights for using Chinese medicine to regulate circadian rhythms and prevent lung cancer.

肺癌作为发病率及死亡率均居首位的恶性肿瘤，其预防和治疗已成为研究热点，昼夜节律紊乱（CRD）被认为是肺癌发生的重要危险因素，但二者的因果关联尚不明确。

探讨昼夜节律紊乱与肺癌发生风险之间的因果关系及可能机制，并进行潜在干预中药预测。

通过UK Biobank等网站获取白天小睡、白天嗜睡、短睡眠时间、长睡眠时间、时间型、失眠及早起的全基因组关联研究（GWAS）数据，通过IEU Open GWAS数据库获取总体肺癌、肺腺癌（LUAD）、肺鳞状细胞癌（LUSC）、小细胞肺癌（SCLC）的GWAS数据，进行孟德尔随机化（MR）分析，以逆方差加权法（IVW）作为主要分析方法评估昼夜节律紊乱与肺癌发生的因果关系。根据单核苷酸多态性（SNPs）定位，并通过蛋白质互作（PPI）网络分析筛选核心基因，进行功能富集分析及生存分析。将核心基因上传至Coremine数据库查找具有潜在干预作用的中药，统计中药性味归经及功效，并筛选出核心中药，使用TCMSP及BATMAN-TCM数据库获得核心中药的关键成分，运用分子对接验证潜在中药关键成分与核心基因的结合能力。

失眠（OR=1.149，95%CI=1.074~1.232，P=0.013）、短睡眠时间（OR=1.462，95%CI=1.033~2.061，P=0.031）与肺癌，失眠（OR=1.181，95%CI=1.061~1.322，P=0.001）、短睡眠时间（OR=1.563，95%CI=1.024~2.401，P=0.038）、白天嗜睡（OR=4.033，95%CI=1.062~15.434，P=0.042）与LUAD，失眠（OR=1.152，95%CI=1.028~1.281，P=0.001）与LUSC，短睡眠时间（OR=1.952，95%CI=1.120~3.383，P=0.017）与SCLC存在因果关联；筛选出139个核心基因，主要富集在G蛋白偶联受体（GPCR）、丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇-3-激酶（PI3K）/蛋白激酶B（Akt）等通路，排名前5的核心基因包括：组蛋白乙酰转移酶P300（EP300）、甘油醛-3-磷酸脱氢酶（GAPDH）、G蛋白亚基β1（GNB1）、G蛋白亚基γ13（GNG13）、肿瘤坏死因子（TNF），其中EP300表达量与LUAD、LUSC、SCLC患者生存时间呈正相关（P<0.05）；CNB1表达量与LUAD患者生存时间呈负相关，与SCLC患者生存时间呈正相关（P<0.05）；GAPDH、GNG13、TNF表达量与LUAD患者生存时间呈负相关（P<0.05）。筛选出水牛角、丹参、鱼脑石、黄芩、郁金、黄芪、灵芝、人参等共40味中药，药味以甘为主，苦、辛次之，药性寒为主，温、平次之，归经多归肝、脾、肺、胃、心、肾经，功效以补气、活血化瘀、清热解毒为主；筛选出水牛角、丹参、三七、黄芩、郁金、姜黄、玉米须、灵芝共8味核心中药，分子对接显示，与核心靶基因有良好的结合效能（结合能<-4 kcal/mol）。

昼夜节律紊乱与肺癌存在因果关系，其作用机制与GCPR、MAPK、PI3K/Akt等通路相关，所预测中药可为中医药调复昼夜节律防治肺癌提供参考依据。