Objective To evaluate the causal associations of gut microbiota, immune cells and serum metabolites with idiopathic pulmonary fibrosis (IPF) based on the multi-omics Mendelian randomization (MR) framework, screen core causal genes, and predict intervening traditional Chinese medicine (TCM) and compounds, so as to provide genetic evidence for the early diagnosis and TCM intervention of IPF. Methods Genetic instrumental variables (IVs) of gut microbiota, serum metabolites and immune cells were extracted, and their causal associations with IPF were analyzed by two-sample MR. Adjacent genes of IVs were annotated to obtain the "microbiota-immunity-metabolism" causal gene set. Integrated with IPF transcriptome data, candidate causal genes were screened by differentially expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA). Diagnostic models were constructed by machine learning to screen core genes. Immune cell infiltration and single-cell RNA sequencing profiles were analyzed. Potential intervening TCM and compounds were predicted via Comparative Toxicogenomics Database (CTD) and Integrated Traditional Chinese Medicine Database (ITCM), followed by molecular docking verification. Results Two-sample MR identified 2 gut microbiota taxa (Lactobacillaceae as protective factor, Proteobacteria as risk factor), 19 immune cell phenotypes (nine protective, ten risk) and 26 serum metabolites (12 protective, 14 risk) that were significantly causally associated with IPF (P < 0.05). A total of 21 candidate causal genes were obtained by integrated analysis, and 5 core genes were screened by machine learning: adaptor protein complex 5 subunit mu 1 (AP5M1), SRY-box transcription factor 11 (SOX11), zinc finger and MIZ-type containing 2 (ZMIZ2), fragile histidine triad (FHIT) and cyclin dependent kinase 6 (CDK6), all with potential diagnostic value. Immune infiltration showed increased activated mast cells and monocytes, and decreased M0/M2 macrophages and activated natural killer cells in IPF tissues. Single-cell analysis revealed the highest enrichment of FHIT in multiple cell types. A total of 150 kinds of potential intervention Chinese medicine were screened. The high frequency Chinese medicine included Sangbaipi (Mori Cortex), Yuejihua (Rosae Chinensis Flos), Yanhusuo (Corydalis Rhizoma), etc. The active ingredients included kaempferol, naringenin, wogonin, sanguinarine, etc. Molecular docking confirmed that the core compound could stably bind to the target. Conclusions This study reveals the causal associations of gut microbiota, immune cells and serum metabolites with IPF, and identifies AP5M1, SOX11, ZMIZ2, FHIT and CDK6 as potential candidate diagnostic biomarkers for IPF. It also predicts the potential intervention value of active compounds such as kaempferol, naringenin and palmatine, as well as TCM including Morus alba and Rosa chinensis, providing genetic evidence and theoretical support for the diagnosis and treatment of IPF.

idiopathic pulmonary fibrosis  /  Mendelian randomization  /  gut microbiota  /  immune cells  /  serum metabolites  /  diagnostic markers  /  Mori Cortex  /  Rosae Chinensis Flos  /  kaempferol  /  naringenin  /  wogonin  /  sanguinarine