Genetic variation perspective reveals potential drug targets for subtypes of endometrial cancer.

The study aims to identify potential drug targets for endometrial cancer (EC) subtypes through a Mendelian randomization (MR) approach, assessing their clinical relevance. We utilized genetic instruments for 4,907 plasma proteins from the deCODE Genetics study dataset, and data with EC (n = 12,906) from a genome-wide study (GWAS) meta-analysis in European populations for MR analyses. Complementary analyses included protein-protein interactions (PPI) network analysis, therapeutic efficacy evaluation, differential gene expression assessment, and prognosis evaluation. The expression levels of key drug targets were quantitatively measured at both the transcriptional and translational stages utilizing reverse transcription quantitative PCR (RT-qPCR) and immunohistochemistry (IHC). Additionally, we analyzed various clinicopathological features. Five drug targets for EC (CBR3, GSTO1, HHIP, IGF2R, and MMP10), seven for endometrioid subtypes (ACAP2, CBR3, GSTO1, HHIP, IGF2R, MMP10, and TLR2), and seven for non-endometrioid subtypes (CST3, DNAJB14, FSTL5, GMPR2, IFI16, MAPK9, and NEO1) were identified. Among these, IGF2R (OR = 1.165; 95% CI 1.067-1.272; p = 1.046 × 10) and CST3 (OR = 0.523; 95% CI 0.339-0.804; p = 7.010 × 10) were highlighted as key drug targets with causal evidence both at transcriptional and translational levels. This study preliminarily confirms that IGF2R and CST3 may serve as novel targets for the treatment of EC, providing a foundational reference for innovative clinical approaches to this disease.