The Sensitive Genes for Cervical Cancer: Two-Sample Mendelian Randomization with Experimental Validation

Rong Zhang,1– 4,* Shengjun Chai,1– 4,* Qihang Chen,1– 5 Jiaming Lai,1– 4,6 Chunmei Cai1– 4 1Research Center for High Altitude Medicine, Qinghai University Medical College, Xining, Qinghai, People’s Republic of China; 2Key Laboratory of the Ministry of High Altitude Medicine, Qinghai University Medical College, Xining, Qinghai, People’s Republic of China; 3Key Laboratory of Applied Fundamentals of High Altitude Medicine, (Qinghai-Utah Joint Key Laboratory of Plateau Medicine), Qinghai University Medical College, Xining, Qinghai, People’s Republic of China; 4Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University Medical College, Xining, Qinghai, People’s Republic of China; 5Department of Biotechnology, College of Ecological and Environmental Engineering, Qinghai University, Xining, People’s Republic of China; 6Physical Engineering Department, The Fifth People’s Hospital of Qinghai Provincial (Provincial Cancer Hospital), Xining, Qinghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunmei Cai, Email [email protected]: Cervical cancer, the fourth leading cause of female cancer mortality globally, faces treatment limitations due to drug resistance and few therapeutic options. This study seeks to identify novel therapeutic targets to address this urgent clinical need.Methods: Our team identified differentially expressed genes (DEGs) in cervical cancer using gene expression omnibus (GEO) datasets. Subsequently, Mendelian randomization (MR) analysis identified causal gene–cancer relationships, followed by enrichment analysis and The Cancer Genome Atlas (TCGA) validation. Finally, we further validated the functions of the selected target genes in cervical cancer cells and analyzed their Gene Set Enrichment Analysis (GSEA) results, drug sensitivity, and prognostic value.Results: We identified 2,801 upregulated and 1,646 downregulated DEGs. MR analysis identified 21 key cervical cancer-associated genes (14 upregulated, 7 downregulated), with TCGA validation confirming significant differential expression patterns. Among them, few studies have examined these core genes, particularly MERTK and SERPINF1, in cervical cancer. Experiments showed that MERTK and SERPINF1 play a role in cervical cancer. These genes help cancer cells grow, spread, and invade surrounding tissue. Mechanistically, MERTK regulates immune infiltration, whereas SERPINF1 modulates chromosomal activity. Clinically, SERPINF1 enhances overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in individuals with cervical cancer. Moreover, we discovered that several commonly used drugs for cervical cancer treatment, like paclitaxel, showed high efficacy against MERTK and SERPINF1.Conclusion: Our study uncovers MERTK and SERPINF1 as critical regulators of cervical cancer progression and survival, offering mechanistic insights into their roles in tumor behavior and the immune microenvironment. These findings provide a foundation for precision therapies, with SERPINF1 restoration and MERTK inhibition as promising strategies. Clinical translation of these targets could address current treatment limitations.Keywords: Mendelian randomization, cervical cancer, MERTK, SERPINF1, experimental validation