Exploring therapeutic targets for hepatocellular carcinoma through druggable genes

Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related mortality worldwide. Mendelian randomization (MR) has emerged as a powerful approach for therapeutic target identification in HCC. In this study, we applied two-sample MR to assess the causal effects of multiple genes on HCC risk. Replication analyses integrated summary-data-based MR, Bayesian co-localization, and protein-protein interaction networks with druggability assessment to prioritize targets. Single-cell RNA sequencing validated cell-type-specific expression patterns in T cells, endothelial cells, and hepatocytes. MR-, summary-data-based MR-, and co-localization-based approaches identified target genes associated with HCC risk, comprising 3 first-level targets (HLA-DPA1, MBTPS1, and TIMP3), 2 second-level targets (TNXB and HSD17B11), and also 4 tertiary targets (HLA-DPB1, PLD2, KLHL8, and TGFBR1). All in all, this research identifies several potential therapeutic targets relevant to the risk of HCC and provides new insights into the identification of therapeutic agents for the treatment of HCC.