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High-throughput omics technologies have begun revolutionizing our understanding of the molecular mechanisms driving cardiac fibrosis and are providing unprecedented insights into its heterogeneity and progression. This review provides a comprehensive analysis of how techniques\u2014encompassing genomics, epigenomics, transcriptomics, proteomics, and metabolomics\u2014are providing insight into our understanding of cardiac fibrosis. Genomic studies have identified novel genetic variants and regulatory networks associated with fibrosis susceptibility and progression, and single-cell transcriptomics has unveiled distinct cardiac fibroblast subpopulations with unique molecular signatures. Epigenomic profiling has revealed dynamic chromatin modifications controlling fibroblast activation states, and proteomic analyses have identified novel biomarkers and potential therapeutic targets. Metabolomic studies have uncovered important alterations in cardiac energetics and substrate utilization during fibrotic remodeling. The integration of these multi-omic data sets has led to the identification of previously unrecognized pathogenic mechanisms and potential therapeutic targets, including cell-type-specific interventions and metabolic modulators. We discuss how these advances are driving the development of precision medicine approaches for cardiac fibrosis while highlighting current challenges and future directions in translating multi-omic insights into effective therapeutic strategies. This review provides a systems-level perspective on cardiac fibrosis that may inform the development of more effective, personalized therapeutic approaches for heart failure and related cardiovascular diseases.<\/jats:p>","DOI":"10.1161\/circresaha.124.325402","type":"journal-article","created":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T14:18:28Z","timestamp":1743085108000},"page":"773-802","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":119,"title":["Cardiac Fibrosis in the Multi-Omics Era: Implications for Heart Failure"],"prefix":"10.1161","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4790-5283","authenticated-orcid":true,"given":"Rachad","family":"Ghazal","sequence":"first","affiliation":[{"name":"Departments of Cardiovascular Diseases (R.G., N.L.P.), Mayo Clinic, Rochester, 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