Deciphering the causal relationships between plasma metabolites, peripheral cells, inflammatory factors and DLBCL for...

Diffuse large B-cell lymphoma (DLBCL) is defined as a highly heterogeneous type of lymphoma which lacks specific biomarkers and drug targets. Past studies revealed changes in plasma metabolites, immune cells and inflammatory factors in the development of DLBCL, yet findings remain inconsistent. Our study aims to elucidate the mediating effects of peripheral cells and inflammatory factors on the relationship between metabolites and DLBCL, and offer therapeutic targets for DLBCL treatment.

We evaluated the association between plasma metabolites, peripheral cells, inflammatory factors and DLBCL risk using two-sample Mendelian randomization (MR) analysis. The proportion of peripheral cells and inflammatory factors in the metabolite-DLBCL axis was further calculated. Sensitivity analyses were conducted to validate the robustness of the results. Besides, summary data-based Mendelian randomization (SMR) analysis and heterogeneity in dependent instruments (HEIDI) test were performed to identify potential drug targets. Further more, in silico docking and molecular dynamic (MD) simulation studies were presented to elucidate the mode of interaction of the top predicted drugs.

MR analysis identified a total of 52 plasma metabolites, 58 peripheral cells and 8 inflammatory factors that were genetically associated with DLBCL. We subsequently identified 6 mediated relationships, with 5 immune cells acting as potential mediators between 6 metabolites and DLBCL. Sensitivity analyses confirmed the robustness of these associations. Further SMR analysis and HEIDI test revealed 5 target genes existed correlation with DLBCL-related metabolites. Additionally, stable drug-target complexes were identified by utilizing molecular docking and dynamic simulation.

This study revealed a significant causal link between plasma metabolites, peripheral cells, inflammatory factors and DLBCL. It remarkably enhances our understanding of the interplay between immune responses, metabolites and DLBCL risk, providing insights into the development of therapeutic strategies from the metabolite-immune axis alternation perspectives.