Genomics and Multi-Omics Perspectives on the Pathogenesis of Cardiorenal Syndrome.

BACKGROUND: Cardiorenal syndrome (CRS) reflects bidirectional heart-kidney injury whose mechanisms extend far beyond hemodynamics. High-throughput genomics and multi-omics now illuminate the molecular circuits that couple cardiac and renal dysfunction. METHODS: We narratively synthesize animal and human studies leveraging transcriptomics, proteomics, peptidomics, metabolomics, and non-coding RNA profiling to map convergent pathways in CRS and to highlight biomarker and therapeutic implications. RESULTS: Across acute and chronic CRS models, omics consistently converge on extracellular matrix (ECM) remodeling and fibrosis (e.g., FN1, POSTN, collagens), immune-inflammatory activation (IL-6 axis, macrophage/complement signatures), renin-angiotensin-aldosterone system hyperactivity, oxidative stress, and metabolic/mitochondrial derangements in both organs. Single-nucleus and bulk transcriptomes reveal tubular dedifferentiation after cardiac arrest-induced AKI and myocardial reprogramming with early CKD, while quantitative renal proteomics in heart failure demonstrates marked upregulation of ACE/Ang II and pro-fibrotic matricellular proteins despite near-normal filtration. Human translational data corroborate these signals: urinary peptidomics detects CRS-specific collagen fragments and protease activity, and circulating FN1/POSTN and selected microRNAs (notably miR-21) show diagnostic potential. Epigenetic and microRNA networks appear to integrate these axes, nominating targets such as anti-miR-21 and anti-fibrotic strategies; pathway-directed repurposing exemplifies dual-organ benefit. CONCLUSIONS: Genomics and multi-omics recast CRS as a systems disease driven by intertwined fibrosis, inflammation, neurohormonal and metabolic programs. We propose a translational framework that advances (i) composite biomarker panels combining injury, fibrosis, and regulatory RNAs; (ii) precision, pathway-guided therapies; and (iii) integrated, longitudinal multi-omics of well-phenotyped CRS cohorts to enable prediction and personalized intervention.