Dissecting causal relationships between inflammatory factors, plasma metabolites, and nonalcoholic fatty liver disease: a mediating Mendelian randomization study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of the global adult population, is a metabolic-associated hepatic disorder characterized by the interplay between inflammation and metabolism. Although evidence linking inflammatory factors and plasma metabolites to NAFLD progression, their causal relationships and mediating mechanisms remain unclear.

METHODS: This study employed a bidirectional Mendelian randomization (MR) approach combined with mediation analysis to investigate the causal relationships between inflammatory factors, plasma metabolites, and NAFLD. Summary data for 91 inflammatory factors and 1400 plasma metabolites were extracted from the genome-wide association studies databases and analyzed using MR. Mediation analysis was performed to examine whether the nine selected metabolites mediated the relationship between the eight inflammatory factors and NAFLD. All the analyses included tests for heterogeneity and pleiotropy.

RESULTS: This study identified 11 inflammatory factors and 110 plasma metabolites that were significantly associated with NAFLD. Mediation analysis revealed that specific metabolites, including pregnenetriol disulfate, alanine: asparagine ratio, and X-21471, mediate the relationship between inflammatory factors and NAFLD. Notably, X-21471 was identified as a shared mediator of both tumor necrosis factor receptor superfamily member 9 (TNFRSF9) and CCL20.

CONCLUSION: This integrative MR mediation analysis delineates an inflammation-metabolism-NAFLD axis, in which specific metabolites (X-21471, pregnenetriol disulfate) transmit pro-inflammatory signals (TNFRSF9/CCL20) involved in NAFLD pathogenesis. These findings suggest that combined targeting of TNFRSF9 and X-21471 may represent a precise preventive strategy for high-risk populations with metabolic comorbidities.