SPP1 as a Critical Regulator of Cardiac Cell Reprogramming Following Myocardial Infarction Through Single-Cell Transcriptomic Analysis

<h4>Background</h4>Cardiovascular mortality remains predominantly driven by acute myocardial infarction (AMI), necessitating comprehensive elucidation of mechanisms governing cardiomyocyte reprogramming for therapeutic advancement. Characterizing molecular dynamics throughout cardiac repair processes presents substantial methodological challenges.<h4>Methods</h4>We employed a comprehensive analytical framework combining bulk and single-cell RNA sequencing datasets from AMI patients, utilizing 26 distinct machine learning algorithms to delineate critical regulatory gene signatures associated with cardiac repair. Gene prioritization was achieved through differential expression profiling coupled with consensus clustering methodologies. Functional validation experiments in H9c2 cardiomyoblast cellular models demonstrated that enhanced SPP1 expression is associated with augmented cellular viability and stimulated cardioprotective factor release, though these findings require validation in more physiologically relevant systems.<h4>Results</h4>Machine learning architectures successfully identified robust cardiomyocyte reprogramming signatures correlating with cardiac functional restoration. Consensus clustering analysis of 276 genes revealed two phenotypically distinct repair subtypes demonstrating divergent recovery trajectories (<i>p</i> < 0.001). Enhanced-recovery clusters exhibited upregulated proliferation markers alongside intensified angiogenic signaling cascades. SPP1 demonstrated exceptional predictive capacity (AUC = 0.896), with experimental validation suggesting its potential functional role in promoting cellular survival, proliferation, and secretion of cardioprotective mediators (VEGF, IGF-1; all <i>p</i> < 0.05).<h4>Conclusion</h4>This machine learning-driven approach successfully identified novel candidate prognostic biomarkers and potential therapeutic targets for cardiac repair interventions, substantially advancing mechanistic understanding of postinfarction cardiac remodeling processes. These findings generate testable hypotheses requiring validation in independent clinical cohorts and more physiologically relevant experimental systems.