Lipid metabolite pathways in idiopathic pulmonary fibrosis:A Mendelian randomization and regulatory network analysis

Wan Naihui; Zhuang Yi; Zhong Guanning; Dai Jinghong

doi:10.3969/j.issn.1671-6450.2026.01.014

Abstract：Objective This study aimed to identify lipid metabolites associated with the risk of idiopathic pulmonary fibrosis(IPF)and investigate their upstream regulatory proteins.Methods Lipid metabolites were selected as candidates based on two published genome-wide association studies(GWAS)on metabolites along with the Lipid Maps,HMDB,and SwissLipids databases.The FinnGen cohort and UK Biobank cohort were used as the discovery cohort and replication cohort for IPF,respectively.Two-sample Mendelian randomization(MR)was utilized to assess the causal associations between lipid metabolites and IPF.Cochran's Q,MR-Egger,and colocalization analyses were performed to evaluate the robustness of the results.Overlapping proteins were screened by integrating IPF lung tissue proteomics data with transcriptomics data from the GEO dataset GSE70866.Subsequent MR was conducted to verify causal associations between candidate proteins and lipid me-tabolites.Results MR analysis identified two lipid metabolites significantly associated with IPF in the discovery cohort:1-oleoyl-2-linoleoyl-sn-glycerol(18∶1/18∶2)(OR=0.659,P=0.041)and isobutyrylcarnitine(C4)(OR=1.165,P=0.025).Cochran's Q and MR-Egger excluded heterogeneity and pleiotropy(P＞0.05),and the posterior probability of Bayesian colo-calization PPH4=92.2％.Multi-omics analysis screened a total of 132 candidate regulatory proteins with GWAS data,inclu-ding NT5E(OR=1.000,P=0.004),RNASET2(OR=1.000,P=0.013),MYL3(OR=0.998,P=0.003),SERPIND1(OR=0.999,P=0.035),PLG(OR=1.000,P=0.002),and CKAP4(OR=1.000,P=0.002).Conclusion A decreased level of 1-oleoyl-2-linoleoyl-sn-glycerol is associated with an elevated risk of IPF,and its level may be regulated by the following pro-teins:NT5E,RNASET2,MYL3,SERPIND1,PLG,CKAP4,and ITIH1.