Multi-omics data reveal the origin of cardiac myxoma.

Cardiac myxoma, the most common primary heart tumor, remains poorly understood at the molecular level. Here, we combined single-nucleus RNA sequencing, third-generation transcriptomics, and untargeted metabolomics to dissect its origin and pathology. Single-cell analyses demonstrate an endothelial origin driven by aberrant endothelial-to-mesenchymal transition (EndMT), with pseudotime and RNA-velocity tracing a continuum from endothelial-like to mesenchymal-like and metabolically active states. We identify two distinct myxoma subtypes: Subtype 1, marked by MAPK/WNT/EGFR pathway activation, and Subtype 2, characterized by ribosomal and oxidative phosphorylation signatures alongside immune-evasive programs. Third-generation data highlight extracellular matrix remodeling and endothelial signaling, while metabolomics reveal dysregulated purine, nicotinic acid, and nicotinamide metabolism. Notably, MET-PTK2 signaling emerges as a potential driver of tumor initiation and progression. These integrated findings define the cellular architecture and metabolic adaptations of cardiac myxoma and lay the foundation for future interventions.