Relationships between immune cells, blood metabolites, and intrahepatic cholangiocarcinoma: a Mendelian randomization study with experimental validation.

INTRODUCTION

Increasing studies have found links between immune traits and intrahepatic cholangiocarcinoma (ICC). However, the presence of confounding variables makes it difficult to determine if this correlation shows a real cause-and-effect relationship.

METHODS

To ascertain the genetic association between immune cell profiles and the risk of ICC, we employed two-sample Mendelian randomization (MR) to figure out the potential therapeutic targets. A mediation analysis was performed to identify potential blood metabolite mediators, thereby elucidating the underlying biological mechanisms. The inverse variance weighted method was used as the major analytical tool, with strict sensitivity analyses to account for horizontal pleiotropy and data heterogeneity.

RESULTS

Out of the immunological profiles examined, a trio of unique traits were identified as being highly associated with the risk of ICC. Elevated counts of activated CD4 regulatory T cells (OR = 1.0005, 95% CI = 1.0002-1.0008, p = 0.0013), CD16 on CD14- CD16+ monocytes (OR = 1.0003, 95% CI = 1.0001-1.0006, p = 0.0021), and CD16 on CD14+ CD16+ monocytes (OR = 1.0004, 95% CI = 1.0001-1.0008, p = 0.0087) were identified as risk factors for the development of ICC. Sensitivity analysis revealed no horizontal pleiotropy or heterogeneity. Mediation research reveals that N-acetylleucine and fructosyllysine levels may act as major molecular mediators. Exploratory experiments targeting the DLAT-leucine metabolic axis in HuCC-T1 and RBE cells revealed that disrupting this pathway significantly impairs tumor cell proliferation and migration.

CONCLUSION

Through two-sample MR analysis, this study demonstrated a causal link between specific immune-cell phenotypes and ICC development. We also identified N-acetylleucine as a vital metabolic link between immune traits and ICC. In vitro experiments confirmed these findings. We observed that knocking down DLAT effectively suppressed both the migratory and proliferative potential of ICC cells.