Role of Dendritic Cells in Mediating the Effect of Growth Differentiation Factor 15 on Nonalcoholic Fatty Liver Disease: Insights From Causal Inference and Single‐Cell Profiling

Background Nonalcoholic fatty liver disease (NAFLD) represents one of the most prevalent chronic liver conditions worldwide. Previous studies have highlighted an association between circulating growth differentiation factor 15 (GDF‐15) levels and NAFLD, as well as the involvement of immune cells in its pathogenesis and progression. However, the causal relationships remain unclear. Methods We obtained summary‐level data for circulating GDF‐15 levels, NAFLD, and 731 immune cell phenotypes from large‐scale genome‐wide association studies (GWAS) and the FinnGen database. Mendelian randomization (MR) analysis was employed to explore the causal relationship between circulating GDF‐15 levels and NAFLD. Additionally, a two‐step MR approach was utilized to identify and assess the mediatory role of immune cells in this association. Finally, single‐cell RNA sequencing analysis (scRNA‐seq) was performed to validate the proportions of CD123 + dendritic cell (DC) subsets in NAFLD progression. Results Two‐sample MR analysis revealed that elevated levels of GDF‐15 are associated with an increased risk of NAFLD (OR = 1.16; 95% confidence interval [CI] = 1.03–1.30; p = 0.017), and replication analysis further confirmed the stability of these findings (OR = 1.10; 95% CI = 1.01–1.20; p = 0.037). Mediation analysis identified that CD123 on plasmacytoid DCs (DCs), CD123 on CD62L+ plasmacytoid DCs, CD80 on plasmacytoid DCs, and CD80 on CD62L+ plasmacytoid DCs mediate the causal effect of GDF‐15 on NAFLD. Sensitivity analyses and bidirectional MR further ensured the robustness of these findings. Single‐cell analysis further validated these results. Conclusions Our findings propose a causal relationship between GDF‐15 and NAFLD mediated by DCs, offering novel insights for potential therapeutic and preventive strategies for NAFLD.