Exploring druggable targets and inflammation-mediated pathways in cancer: a Mendelian randomization analysis integrating transcriptomic and proteomic data.

Background: Cancer remains a predominant global health challenge, necessitating the ongoing exploration of novel biomarkers and therapeutic targets to improve diagnosis and treatment.

Methods: By integrating expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) data with genome-wide association studies (GWAS) data, we performed Mendelian randomization (MR) analysis to identify potential druggable targets at the gene expression and protein levels for multiple cancers. We conducted mediation analysis to explore whether inflammatory factors mediate the pathways linking identified druggable targets to cancer. Phenome-wide MR analysis, drug prediction, and molecular docking were employed to evaluate the medicinal potential.

Results: We finally identified five druggable targets: CDKN1A, FES, and PDIA3 were associated with breast cancer, whereas TP53 and VAMP8 were associated with prostate cancer. Mediation analysis identified six inflammatory proteins as potential mediators in the causal pathways from these druggable targets to cancer: caspase 8, interleukin-1-alpha, C-X-C motif chemokine 1, C-C motif chemokine 23, TNF-related apoptosis-inducing ligand, and interleukin-6. Subsequent analyses further provided evidence supporting the pharmaceutical potential of these five targets.

Conclusions: Our study identified five druggable targets causally associated with breast and prostate cancers, with six inflammatory proteins acting as potential mediators, providing novel insights into the treatment of these cancers.