Plasma Proteomic Insights into the Digestive System Disorders Unveil Causal Associations and Drug Repurposing Targets

Digestive system disorders (DSDs) are prevalent and burdensome conditions worldwide. The human proteome serves as a primary source for designing disease treatment targets and holds great potential for drug repurposing. We applied Mendelian randomization analyses to examine the genetic associations between 2321 plasma proteins and 47 DSDs using data from the FinnGen project, identifying 12 causal proteins and validating four (Tripartite Motif Containing 40, Sulfotransferase Family 2A Member 1, Peptidase Inhibitor 16, MHC Class I Polypeptide-Related Sequence B) of them in the UK Biobank. Mediation analysis showed that SULT2A1 may increase the risk of cholelithiasis by reducing 25-hydroxyvitamin D levels. Molecular interaction simulations indicated that the interaction between SULT2A1 and 25-hydroxyvitamin D is comparable to that with the defined substrate 24-OHChol-24-sulfate. We found that elevated levels of SULT2A1 may increase metabolism of approved drugs for cholelithiasis (i.e., ursodeoxycholic acid and chenodeoxycholic acid) by binding deoxycholic acid, thus reducing drug efficacy. We applied the AlphaFold3 strategy to simulate interactions between SULT2A1 and 10,052 small molecules, identifying 5 molecules that may competitively bind to SULT2A1, potentially enhancing the treatment efficacy of deoxycholic acid for cholelithiasis. Overall, our study reveals several causal associations between plasma proteins and DSDs and identifies SULT2A1 as a promising drug repurposing target for cholelithiasis.

The online version contains supplementary material available at 10.1007/s43657-025-00231-y.