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Decoding atherosclerosis through lactylation: multi-omics integration with experimental validation
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DOI：10.3389/fcell.2026.1742425.png)
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Abstract
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BackgroundAtherosclerosis (AS) remains a major cause of cardiovascular morbidity and mortality. Lactylation—a recently described post-translational modification linking cellular metabolism to gene regulation—has been implicated in vascular inflammation; yet its roles in AS are not fully defined.MethodWe modelled AS by exposing HUVECs to oxidised LDL and performed data-independent proteomics. Public AS transcriptomes were integrated and batch-corrected; lactylation-related genes (LRGs) were profiled; consensus clustering and WGCNA defined subtypes/modules. Candidate biomarkers were prioritised by intersecting proteomic; differential and network features; then evaluated using an ensemble of 12 machine-learning algorithms with cross-validation and external validation. Immune infiltration (CIBERSORT) and single-cell data characterised immune contexts. Connectivity Map; molecular docking and molecular dynamics (MD) explored therapeutics. Core genes were validated by RT-qPCR; Western blotting and immunofluorescence in Apoe−/− mice.ResultsProteomics identified 472 differentially expressed proteins; GEO analyses yielded 2; 544 DEGs and WGCNA 2; 059 module genes; converging on 25 candidates. The top ensemble (LASSO + GBM) achieved a mean AUC 0.979 across training and external sets; nominating UAP1; NRP1; QPRT and NDST1 as hub genes. These genes associated with immune-cell infiltration and showed prominent single-cell expression in macrophages and smooth muscle cells. RT-qPCR in vivo showed NRP1/NDST1/QPRT upregulated and UAP1 downregulated versus controls (all P < 0.05); WB/IF confirmed higher NRP1 and lower UAP1 protein abundance. CMap analysis suggested several candidate compounds. Among them; rivaroxaban was prioritised for further in silico evaluation because NRP1 emerged as a validated hub gene; and docking and molecular dynamics simulations supported a stable predicted interaction between rivaroxaban and NRP1.ConclusionUAP1; NRP1; QPRT and NDST1 represent lactylation-linked biomarkers of AS with diagnostic potential and plausible mechanistic relevance within immune-vascular pathways. Computational screening further prioritised a putative NRP1–rivaroxaban interaction as a hypothesis-generating lead for future experimental validation.
Keywords:
machine learning
proteomics
molecular dynamics
atherosclerosis
lactylation
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