Itaconate modulates myeloid inflammation in myocardial infarction via metabolic and structural reprogramming.

backgroundAcute myocardial infarction (AMI) is a leading cause of mortality worldwide, with sterile inflammation and immune dysregulation driving cardiac injury. Itaconate, a mitochondria-derived immunometabolite synthesized by ACOD1, has emerged as a key regulator of myeloid cell function, exhibiting anti-inflammatory and metabolic effects. However, its role and downstream targets in sterile myocardial inflammation remain poorly understood.

objectiveThis study aimed to systematically dissect the immunometabolic role of itaconate in AMI by identifying itaconate-responsive genes, uncovering their cell-type specificity and functional dynamics, and evaluating their diagnostic and therapeutic potential.

methodsWe established a novel systems-level framework that integrates bulk and single-cell/single-nucleus transcriptomics, network pharmacology, machine learning-based feature selection, and molecular docking. This multi-layered strategy was applied to human and murine datasets covering infarcted cardiac tissue and peripheral immune compartments to identify robust, itaconate-responsive immune targets in AMI.

resultsSingle-cell data show that ACOD1 induction is disease-specific and characteristic of AMI. And we identified 36 itaconate-associated genes enriched in myeloid populations and dynamically regulated during infarction. Among them, MMP9, TLR2, and ANPEP were consistently prioritized by multiply machine learning algorithms, showed robust diagnostic performance across independent cohorts, and exhibited potential binding to itaconate in silico. Single-cell analyses confirmed spatial and temporal regulation of these targets in infarcted myocardium. Functional analyses revealed that 4-octyl-itaconate (4-OI) induced dose- and context-dependent transcriptional programs in myeloid cells, including NRF2 and ATF3 activation.

conclusionsThis study identifies a core immunometabolic program downstream of itaconate in myeloid cells and highlights MMP9, TLR2, and ANPEP as key effectors linking metabolic sensing to inflammation and tissue remodeling in AMI. Our integrative approach offers new insights into context-specific immunomodulation and supports the development of metabolite-guided therapeutic strategies for cardiovascular inflammation.