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Experimental and clinical studies suggest that bilirubin exhibits potent antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective properties that may protect the heart against oxidative stress, ischemia\u2013reperfusion injury, and the progression of cardiovascular diseases, such as heart failure. As an endogenous hormone, bilirubin activates peroxisome proliferator-activated receptor-\u03b1 (PPAR\u03b1), a nuclear receptor that controls energy balance and lipid metabolism. Moderately elevated circulating bilirubin levels have been associated with a reduced risk of coronary artery disease, heart failure, and myocardial infarction; however, the mechanisms underlying bilirubin\u2019s protective effects remain incompletely understood. Conversely, the gut microbiota\u2019s metabolism of bilirubin to urobilin is detrimental, given urobilin\u2019s association with cardiometabolic dysfunction. The therapeutic potential of bilirubin in the management of cardiovascular disease is becoming increasingly apparent, supported by preclinical research and emerging technologies that enhance bilirubin delivery via nanoparticles and methods to elevate plasma bilirubin levels. Collectively, these scientific advancements position bilirubin as a promising, biologically plausible endogenous therapeutic for the prevention and treatment of heart disease.<\/jats:p>","DOI":"10.3390\/biom16050625","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T08:11:14Z","timestamp":1776931874000},"page":"625","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transforming Toxicity into Therapy: Exploring Bilirubin\u2019s Benefits and Its Molecular Role in Cardiac Health and Disease"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8457-9681","authenticated-orcid":false,"given":"Michael I.","family":"Adenawoola","sequence":"first","affiliation":[{"name":"Department of Physiology & Biophysics, Cardiovascular-Renal Research Center, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7344-7469","authenticated-orcid":false,"given":"Zachary A.","family":"Kipp","sequence":"additional","affiliation":[{"name":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7599-1529","authenticated-orcid":false,"suffix":"Jr.","given":"Terry D.","family":"Hinds","sequence":"additional","affiliation":[{"name":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8359-4008","authenticated-orcid":false,"given":"David E.","family":"Stec","sequence":"additional","affiliation":[{"name":"Department of Physiology & Biophysics, Cardiovascular-Renal Research Center, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref_1","first-page":"e41","article-title":"2025 Heart Disease and Stroke Statistics: A Report of US and Global Data from the American Heart Association","volume":"151","author":"Martin","year":"2025","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Vetrano, E., Caturano, A., Nilo, D., Di Lorenzo, G., Tagliaferri, G., Piacevole, A., Donnarumma, M., Iadicicco, I., Picco, S., and Moretto, S.M. 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