Exploring the Causal Relationship between Circadian Rhythm Disorders and Lung Cancer and Potential Interventional Traditional Chinese Medicine postprint

Abstract: Background  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. Objective  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. Methods  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. Results  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. Conclusion  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.