TRP channels in hepatocellular carcinoma: integrative Mendelian randomization and multi-omics analyses highlight MCOLN3/TRPV4 as candidate dual-effect biomarkers.

Background: The causal relationship between Transient receptor potential (TRP) and hepatocellular carcinoma (HCC) remains unclear. Our study aimed to identify potential drug targets for HCC within the TRP family using Mendelian randomization (MR).

Methods: The gene expression quantitative trait loci (eQTL) data for TRP was sourced from eQTLGen Consortium. Summary statistics for HCC came from European (nCase = 379, nControl = 475,259) and East Asian population (nCase = 2122, nControl = 159,201). We undertook main MR analysis in the European population using the R package 'TwosampleMR', with significance determined through Bonferroni correction. The East Asian population serves as the validation cohort. Sensitivity analyses include Steiger filtering, bidirectional MR analysis, multivariable MR (MVMR) analysis, and phenotype scanning for further validation of causal relationships.

Results: Main MR analysis had identified two causal TRPs, MCOLN3 (OR = 1.59, 95% CI: 1.24-2.06) and TRPV4 (OR = 0.597, 95% CI: 0.407-0.875). No heterogeneity or pleiotropy was detected. The basal metabolic rate may partially mediate the causal effect of TRPV4 on HCC. Drugs such as cisplatin and Cannabidiol were identified for their potential action on causal TRPs. High expression of MCOLN3 may lead to increased sensitivity to sorafenib, while patients with low expression of MCOLN3 and TRPV4 were more likely to benefit from immunotherapy. Furthermore, we revealed the expression landscape of causal TRPs in HCC by performing integrated multi-omics analyses.

Conclusions: This MR analysis revealed a causal relationship between TRP and HCC, and MCOLN3 and TRPV4 were potential drug targets. They also served as potential molecular biomarkers for the efficacy of immunotherapy and/or targeted therapy, providing a strong theoretical basis for the clinical application of TRPs.