The correlation between cathepsins and pulmonary arterial hypertension (PAH) is well-established, but the causative link between them remains uncertain. This study aimed to explore the causal role of circulating metabolites mediating cathepsins in PAH using Mendelian randomization (MR). A 2-sample 2-step MR method was used to identify causal relationship between cathepsins and PAH; causal relationship between circulating metabolites and PAH; and mediated effects of these circulating metabolites. GWAS summary statistics on circulating metabolites were from the Canadian longitudinal study on aging cohort, human plasma cathepsins from The INTERVAL study, and PAH from FinnGen version R10. Two-sample MR analyses involving 9 cathepsins (cathepsin B, E, F, G, H, L2, O, S, and Z). Cathepsin S was associated with high risk of PAH (OR: 1.346, 95% CI: 1.039-1.742, P = .024), and positively with circulating metabolite 1-oleoylglycerol (18:1) levels (OR: 1.062, 95% CI: 1.018-1.108, P = .005). Finally, mediation analysis showed evidence of mediated effect of cathepsin S on PAH through 1-oleoylglycerol (18:1) levels (OR: 0.062, CI: 0.0183-0.106) with a mediated proportion of 20.9% of the total effect. This study reveals cathepsin S increases the risk of PAH mediating by circulating metabolite 1-oleoylglycerol (18:1) levels.
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