Cathepsins Influence Metastatic Liver Cancer via Plasma Proteins: a Mendelian randomization Study

Abstract Background: Cathepsins (CTSs), lysosomal cysteine proteases, have been reported to play roles in the initiation, infiltration, and dissemination of tumors in previous researches. However, the precise causal relationship between CTSs and metastatic liver cancer (MLC) remains undetermined. This study aimed to investigate the potential causal relationship between CTSs and MLC, as well as to examine the mediating effect of plasma proteins in this relationship, ultimately establishing a causal network among them. Methods: Data were obtained from genome-wide association analysis (GWAS). Inverse variance weighting (IVW), Bayesian weighting (BW), MR-Egger regression, Weighted median (WM) and MR-conmix methods were employed for Mendelian randomization (MR) Analysis. Sensitivity analysis included Cochran's Q test, Mr-Egger intercept, MR-PRESSO test and leave-one-out validation. Results: Univariable MR revealed that an increase in CTSF (cathepsin F), CTSD (cathepsin D), and CSTV (cathepsin V) was associated with a reduced risk of MLC among 11 CTSs. While reverse MR did not yield significant findings. And total of 42 plasma proteins were identified to have a causal relationship with MLC, among which 13 types were found to mediate the association between the 3 CTSs and MLC. Conclusions: Our study suggests a potential causal relationship involving 3 CTSs, 13 plasma proteins, and MLC. These results provide valuable references for disease prediction, targeted therapy and mechanistic research of MLC.