<p>This study investigates the causal relationships between plasma metabolites, immune cell phenotypes, and diabetic foot ulcer (DFU). A Mendelian randomization (MR) study was conducted, which included 731 immune cell phenotypes, 1400 metabolites, and DFU. The primary analytical approach was the inverse variance-weighted method. Sensitivity analyses were performed to assess heterogeneity and pleiotropy, and MR analyses in the reverse direction were conducted to examine the possibility of reverse causation. In addition, a mediation analysis was performed to reveal how metabolites mediate the impact of immune cells on DFU. Through MR, reverse MR and sensitivity analysis, the casualty was found in 17 immune cell phenotypes and 18 metabolites. A total of 15 mediating relationships were identified through mediation analysis, including 9 metabolites and 10 immune cell phenotypes. Among them, the highest mediation proportion was citrulline levels mediating CD24⁺ CD27⁺ AC (absolute count, B cell panel) to DFU, with a proportion of 11.60%. In conclusion, the study identified causal relationships between 10 immune cell phenotypes mediated by 9 metabolites. These discoveries offered fresh perspectives on the processes behind DFU and laid the groundwork for subsequent studies to create specific treatments for DFU.</p>