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Chang Li,1,2,* Zefei Jiang,3,* Jie Bai,4 Mi Li,5 Meihe Li,6 Xiaoling Wu,7 Yan Zhang,8 Bin Li,9 Qingwei Xie,10 Fei Li,11 Maoxing Ran,12 Huimin Dang13 1School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China; 2Department of Gynecology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China; 3Department of Acupuncture, the Third Affiliated Hospital of Yunnan University of Chinese Medicine, Kunming, Yunnan, People’s Republic of China; 4Department of Obstetrics and Gynecology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei, People’s Republic of China; 5School of Stomatology, North China University of Science and Technology, Tangshan, Hebei, People’s Republic of China; 6Department of Renal Transplantation, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 7Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 8Outpatient Department, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 9Department of Imaging, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 10Department of Nuclear Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 11Department of Convalescence, Lintong Rehabilitation and Convalescent Center, Joint Logistic Support Force, Chinese People’s Liberation Army, Xi’an, Shaanxi, People’s Republic of China; 12Graduate School, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People’s Republic of China; 13Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huimin Dang, Email dhm_1213@163.comBackground: Smoking and alcohol consumption have been consistently associated with adverse female reproductive outcomes; however, whether these associations reflect causal effects or are mediated by specific circulating metabolites remains unclear. We aimed to clarify the causal relationships between smoking- and alcohol-related behaviors and female reproductive disorders and to quantitatively assess metabolite-mediated effects.Methods: We conducted a large-scale two-sample Mendelian randomization (MR) study using genome-wide association data from up to 2.7 million individuals. Smoking behaviors (including smoking initiation, cigarette consumption, smoking cessation, and age at initiation) and alcohol consumption were evaluated in relation to multiple female reproductive disorders, including abnormal uterine bleeding, adenomyosis, endometrioid ovarian cancer, ovarian cysts, and female pelvic inflammatory diseases. To elucidate underlying mechanisms, we implemented a two-step MR–based mediation framework to quantify indirect effects through circulating metabolites.Results: Genetically predicted smoking initiation was associated with increased risks of abnormal uterine bleeding, endometrioid ovarian cancer, ovarian cysts, and inflammatory diseases of the female reproductive organs. Higher cigarette consumption was also causally associated with an increased risk of adenomyosis. Mediation analyses identified specific inflammatory and lipid-related metabolites as partial mediators of these associations. In particular, glycoprotein acetyls (GlycA) and four very low-density lipoprotein (VLDL) subtype markers jointly mediated 2.76– 7.61% of the total effect of cigarettes per day on adenomyosis. Similarly, triglycerides across five lipoprotein subclasses mediated 1.08– 1.77% of the total effect of smoking initiation on inflammatory diseases of the female reproductive organs.Conclusion: This study provides genetically informed evidence supporting a potential causal role of smoking-related behaviors in female reproductive disorders. By identifying circulating metabolites as mediators, our findings reveal novel pathways linking smoking to gynecological disease risk and highlight metabolic dysregulation as a clinically relevant target for risk stratification and integrated smoking prevention or cessation strategies.Keywords: mendelian randomization, mediation analysis, smoking, female reproductive diseases, circulating metabolites, GlycA