Mendelian Randomization and Single-Cell Transcriptomic Analyses Implicate PPP1R1B as a Risk Factor of Intrahepatic Cholangiocarcinoma.

Background:PPP1R1B has been implicated in tumor progression in several malignancies; however, population-level genetic evidence supporting its role in intrahepatic cholangiocarcinoma (ICC) remains limited. This study aimed to investigate the association between PPP1R1B and ICC risk and prognosis using genetic and multi-omics analyses. Methods: Multiple public datasets were integrated, including finn-b-C3_LIVER_INTRAHEPATIC_BILE_DUCTS, ebi-a-GCST90018583, eqtl-a-ENSG00000131771, GSE138709, The Cancer Genome Atlas (TCGA)-ICC, and FU-iCCA. Two-sample Mendelian randomization (MR) was performed to evaluate the genetic association between PPP1R1B expression and ICC risk. PPP1R1B expression patterns were further characterized using single-cell and bulk transcriptomic analyses. Expression validation was conducted using TCGA-ICC data and tissue microarray immunohistochemistry. Survival analyses were performed using the FU-iCCA cohort and institutional clinical samples. Results: MR analysis identified PPP1R1B as significantly associated with increased ICC risk (p < 0.05, OR > 1), and sensitivity analyses supported the robustness of the results. Single-cell analysis demonstrated enrichment of PPP1R1B expression in malignant cell populations. Bulk transcriptomic datasets and immunohistochemical validation confirmed elevated PPP1R1B expression in tumor tissues. High PPP1R1B expression was significantly associated with poorer overall survival. Conclusions: Genetic and multi-omics evidence supports PPP1R1B as a risk-associated and potential prognostic biomarker in ICC, providing a translational genomics framework for future biomarker development. These findings complement previously reported functional studies and strengthen the biological relevance of PPP1R1B in ICC.