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Interstitial lung disease (ILD) comprises diverse chronic inflammatory and fibrotic disorders with poorly understood mechanisms and limited diagnostic biomarkers. Growing evidence implicates lipid metabolic reprogramming in ILD pathogenesis, yet integrated metabolomic-transcriptomic analyses remain scarce. We performed combined metabolomic and transcriptomic analysis using publicly available datasets. Plasma metabolite profiles of ILD and lobar pneumonia (LOB) patients were analyzed by NMR-based metabolomics. Multivariate analyses (PCA, PLS-DA, OPLS-DA) identified discriminatory metabolites. KEGG enrichment revealed associated pathways. Transcriptomic data from lung tissue were analyzed for differentially expressed genes, identifying 345 differentially expressed genes (|log2FC| > 0.585, adjusted p < 0.05), integrated with metabolomic data to identify shared pathways. ROC curves evaluated diagnostic performance of key metabolites. To validate the bioinformatic findings, we established a bleomycin (BLM)-induced ILD mouse model with or without high-cholesterol diet (HCD) intervention. RT-qPCR, Western blotting, H&E staining, and Masson's trichrome staining were performed to assess gene expression and histopathological changes in lung tissue. Metabolomic profiling showed clear separation between ILD and LOB samples, driven by alterations in triglyceride-rich lipoproteins, phospholipids, and cholesterol fractions. Seven metabolites were significantly increased in ILD (p < 0.05). Integrated multi-omics identified "lipid and atherosclerosis" as a key shared pathway, encompassing six differential genes (CD36, NFKBIA, PIK3R1, SELP, CCL2, VCAM1) and one differential metabolite (Cholesterol [HDL4]). ROC analysis showed a combined metabolite model achieved AUC of 0.810. Experimental validation confirmed SELP, CCL2, and VCAM1 were upregulated while NFKBIA was downregulated in BLM-treated mice. HCD further aggravated BLM-induced pulmonary fibrosis and markedly elevated the expression of inflammatory cytokines (TNF-α, IL-6, IL-1β) as well as key pathway proteins (SELP, CCL2, VCAM1). This integrated multi-omics analysis reveals a strong link between lipid dysregulation and ILD pathogenesis. Cholesterol fractions, triglycerides, and phospholipids may serve as potential non-invasive biomarkers for ILD, while the lipid and atherosclerosis pathway represents a promising target for therapeutic intervention. Animal experiments further validated that HCD exacerbates ILD via the lipid and atherosclerosis pathway, reinforcing the clinical relevance of cholesterol dysregulation in ILD progression. Our findings provide new insights into the metabolic mechanisms of ILD and establish a foundation for future diagnostic and therapeutic development.