Peroxisome proliferator-activated receptor alpha (PPARα) may serve as a potential target for asthma treatment, but the mechanism is not fully elucidated. Previous studies have shown that PPARα regulates circulating metabolites and influences asthma development. The causal relationship between PPARα, circulating metabolites, and asthma remains unexplored. Hence, our study aimed to investigate the effect of circulating metabolites mediating PPARα activation in asthma by Mendelian randomization (MR).

Data were extracted from GWAS consortia for our research. A two-sample and two-step MR study was conducted to assess the association of PPARα activation with asthma, as well as to explore the potential mediating effects of circulating metabolites in linking PPARα activation with asthma. 

Genetically predicted PPARα activation were associated with reduced risk of asthma (β3=-0.05, P=0.042). Among 123 circulating metabolites, lactate was identified to be associated with both PPARα activation and asthma. PPARα activation were associated with reduced risk of asthma (β1=-0.15, P=0.006). The effect of PPARα activation on asthma through lactate (β2=-0.058, P=0.003), with a mediated proportion of 14.833% ([8.365%-21.301%], P = 0.010) of the total effect.

This study provided further evidence supporting the association of PPARα activation with a decreased risk of asthma. Lactate was identified as a mediator in the causal pathways linking PPARα activation and asthma, and intervention of this factor may be helpful in terms of asthma control. Future research should delve into the mechanistic and clinical aspects to elucidate the mediating effects of circulating metabolites, particularly lactate, in the relationship between PPARα activation and asthma.