{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:17:35Z","timestamp":1790000255627,"version":"4.0.1"},"reference-count":105,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Bilirubin was long regarded primarily as a waste product of haem catabolism, but accumulating experimental and epidemiological evidence suggests that, within an appropriate concentration range, it may contribute to cardiovascular protection through antioxidant, anti-inflammatory, endothelial, metabolic, and mitochondrial effects. Haem oxygenase-1 (HO-1) is a key inducible enzyme in bilirubin formation because it converts haem to biliverdin, which is subsequently reduced to bilirubin. However, HO-1 activation also produces carbon monoxide and ferrous iron, and increased HO-1 expression alone does not demonstrate enhanced bilirubin production or bilirubin-mediated protection. This critical narrative review first examines the biological basis and evidential limits of bilirubin-related cardiovascular protection and then evaluates whether selected plant metabolites and traditional multi-component formulations used in Chinese medicine engage the HO-1\/bilirubin axis in cardiovascular models. Curcumin provides the most direct evidence of pathway engagement because HO activity, circulating bilirubin, pharmacological inhibition, and HO-1 silencing were assessed. Dihydromyricetin shows HO-1-dependent vascular protection, although bilirubin was not measured. For most other metabolites and formulations, the evidence is limited to Nrf2\/HO-1-associated signalling in preclinical models. Material characterisation, dose justification, bioavailability, pharmacokinetics, safety assessment, and direct measurement of haem-catabolic products remain inconsistent. The available data support the HO-1\/bilirubin axis as a biologically plausible link between selected interventions used in Chinese medicine and cardiovascular protection, but direct bilirubin-specific causality remains unproven. Future studies should combine standardised materials, exposure-confirmed dosing, direct quantification of bilirubin and biliverdin,\n                    <jats:italic>HMOX1<\/jats:italic>\n                    \/BVRA manipulation, and product-specific rescue experiments.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1902935","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:30:15Z","timestamp":1789997415000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The HO-1\/bilirubin axis in cardiovascular protection: critical evidence for modulation by plant metabolites and traditional multi-component formulations used in Chinese medicine"],"prefix":"10.3389","volume":"17","author":[{"given":"Rui","family":"Zhang","sequence":"first","affiliation":[{"name":"Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]},{"name":"The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Wang","sequence":"additional","affiliation":[{"name":"Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]},{"name":"The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Wu","sequence":"additional","affiliation":[{"name":"Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxiu","family":"Qin","sequence":"additional","affiliation":[{"name":"Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianghan","family":"Qi","sequence":"additional","affiliation":[{"name":"Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Yu","sequence":"additional","affiliation":[{"name":"Hubei University of Chinese Medicine","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Hou","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingqing","family":"Hu","sequence":"additional","affiliation":[{"name":"Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1124\/pr.107.07104","article-title":"Pharmacological and clinical aspects of heme oxygenase","volume":"60","author":"Abraham","year":"2008","journal-title":"Pharmacol. Rev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.3390\/antiox10101536","article-title":"Bilirubin as a therapeutic molecule: challenges and opportunities","volume":"10","author":"Adin","year":"2021","journal-title":"Antioxidants"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e021212","DOI":"10.1161\/JAHA.121.021212","article-title":"Bilirubin nanoparticles protect against cardiac ischemia\/reperfusion injury in mice","volume":"10","author":"Ai","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"B4","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"B5","doi-asserted-by":"publisher","first-page":"16093","DOI":"10.1073\/pnas.252626999","article-title":"Biliverdin reductase: a major physiologic cytoprotectant","volume":"99","author":"Baranano","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1016\/j.bbagen.2007.03.005","article-title":"Protective role of unconjugated bilirubin on complement-mediated hepatocytolysis","volume":"1770","author":"Basiglio","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"B7","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.plipres.2012.11.001","article-title":"Bilirubin and beyond: a review of lipid status in Gilbert's syndrome and its relevance to cardiovascular disease protection","volume":"52","author":"Bulmer","year":"2013","journal-title":"Prog. Lipid Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1089\/ars.2013.5659","article-title":"The multifunctional role and therapeutic potential of HO-1 in the vascular endothelium","volume":"20","author":"Calay","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"B9","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1007\/s11373-006-9098-2","article-title":"Tetramethylpyrazine induces heme oxygenase-1 expression and attenuates myocardial ischemia\/reperfusion injury in rats","volume":"13","author":"Chen","year":"2006","journal-title":"J. Biomed. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2506","DOI":"10.1016\/j.bbagen.2015.09.018","article-title":"Ferritin heavy chain mediates the protective effect of heme oxygenase-1 against oxidative stress","volume":"1850","author":"Cheng","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"B11","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1016\/j.freeradbiomed.2008.12.002","article-title":"Antioxidant activity of liver growth factor, a bilirubin covalently bound to albumin","volume":"46","author":"Condezo-Hoyos","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1007\/s00894-023-05720-3","article-title":"Intramolecular hydrogen bonds interactions in the isomers of the bilirubin molecule: DFT and QTAIM analysis","volume":"29","author":"Cruz","year":"2023","journal-title":"J. Mol. Model."},{"key":"B13","first-page":"316","article-title":"Yixin formula regulates the SIRT1\/Nrf2\/HO-1 signalling pathway to ameliorate myocardial ischaemia\u2013reperfusion injury in rats","volume":"44","author":"Dong","year":"2024","journal-title":"Chin. J. Integr. Tradit. West. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"181","DOI":"10.3390\/antiox8060181","article-title":"Targeting heme Oxygenase-1 in cardiovascular and kidney disease","volume":"8","author":"Drummond","year":"2019","journal-title":"Antioxidants"},{"key":"B15","doi-asserted-by":"publisher","first-page":"wrae242","DOI":"10.1093\/ismejo\/wrae242","article-title":"Bilirubin reductase shows host-specific associations in animal large intestines","volume":"18","author":"Dufault-Thompson","year":"2024","journal-title":"ISME J."},{"key":"B16","doi-asserted-by":"publisher","first-page":"64","DOI":"10.2174\/1871530321999210128201259","article-title":"Association between total bilirubin levels and cardio-metabolic risk factors related to obesity","volume":"22","author":"El-Eshmawy","year":"2022","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"B17","doi-asserted-by":"publisher","first-page":"103850","DOI":"10.1016\/j.mcn.2023.103850","article-title":"Bilirubin induces microglial NLRP3 inflammasome activation in vitro and in vivo","volume":"125","author":"Ercan","year":"2023","journal-title":"Mol. Cell. Neurosci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"3675","DOI":"10.3390\/ijms20153675","article-title":"Heme, heme oxygenase, and endoplasmic reticulum Stress-A new insight into the pathophysiology of vascular diseases","volume":"20","author":"G\u00e1ll","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2975","DOI":"10.3390\/molecules26102975","article-title":"Identification of binding regions of bilirubin in the ligand-binding pocket of the peroxisome proliferator-activated Receptor-A (PPARalpha)","volume":"26","author":"Gordon","year":"2021","journal-title":"Molecules"},{"key":"B20","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/s41564-023-01549-x","article-title":"BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen","volume":"9","author":"Hall","year":"2024","journal-title":"Nat. Microbiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2952","DOI":"10.1016\/j.jacc.2017.04.041","article-title":"Traditional Chinese medicine for cardiovascular disease: evidence and potential mechanisms","volume":"69","author":"Hao","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"953205","DOI":"10.3389\/fphar.2022.953205","article-title":"Best practice in the chemical characterisation of extracts used in pharmacological and toxicological research-The ConPhyMP-Guidelines","volume":"13","author":"Heinrich","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2545","DOI":"10.3390\/molecules24142545","article-title":"PPARs as nuclear receptors for nutrient and energy metabolism","volume":"24","author":"Hong","year":"2019","journal-title":"Molecules"},{"key":"B24","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1167\/iovs.65.13.55","article-title":"cRGD-Conjugated bilirubin nanoparticles alleviate dry eye disease Via activating the PINK1-Mediated mitophagy","volume":"65","author":"Huang","year":"2024","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.redox.2015.06.008","article-title":"Bilirubin inhibits the up-regulation of inducible nitric oxide synthase by scavenging reactive oxygen species generated by the toll-like receptor 4-dependent activation of NADPH oxidase","volume":"5","author":"Idelman","year":"2015","journal-title":"Redox Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2843","DOI":"10.1016\/j.biocel.2013.09.014","article-title":"The molecular basis for the immunomodulatory activities of unconjugated bilirubin","volume":"45","author":"Jangi","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/emm.2006.46","article-title":"Comparative effects of curcuminoids on endothelial heme oxygenase-1 expression: ortho-methoxy groups are essential to enhance heme oxygenase activity and protection","volume":"38","author":"Jeong","year":"2006","journal-title":"Exp. Mol. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.jconrel.2021.01.019","article-title":"Bilirubin nanomedicine ameliorates the progression of experimental autoimmune encephalomyelitis by modulating dendritic cells","volume":"331","author":"Kim","year":"2021","journal-title":"J. Control. Release"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3858","DOI":"10.1021\/acs.jproteome.4c00170","article-title":"Proteomics profiling of bilirubin nanoparticle treatment against myocardial ischemia-reperfusion injury","volume":"23","author":"Kim","year":"2024","journal-title":"J. Proteome Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e0243407","DOI":"10.1371\/journal.pone.0243407","article-title":"Relationship between serum bilirubin levels, urinary biopyrrin levels, and retinopathy in patients with diabetes","volume":"16","author":"Kudo","year":"2021","journal-title":"PLoS One"},{"key":"B31","doi-asserted-by":"publisher","first-page":"955","DOI":"10.3390\/cimb47110955","article-title":"Role of anti-inflammatory and antioxidant properties of natural products in curing cardiovascular diseases","volume":"47","author":"Kulkarni","year":"2025","journal-title":"Curr. Issues Mol. Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.exger.2015.09.014","article-title":"Serum total bilirubin levels and coronary heart disease--Causal association or epiphenomenon?","volume":"72","author":"Kunutsor","year":"2015","journal-title":"Exp. Gerontol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"3164","DOI":"10.1073\/pnas.1422373112","article-title":"Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function","volume":"112","author":"Lakhal-Littleton","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B34","doi-asserted-by":"publisher","first-page":"e19804","DOI":"10.7554\/eLife.19804","article-title":"An essential cell-autonomous role for hepcidin in cardiac iron homeostasis","volume":"5","author":"Lakhal-Littleton","year":"2016","journal-title":"Elife"},{"key":"B35","doi-asserted-by":"publisher","first-page":"7460","DOI":"10.1002\/anie.201602525","article-title":"Bilirubin nanoparticles as a nanomedicine for anti-inflammation therapy","volume":"55","author":"Lee","year":"2016","journal-title":"Angewandte Chemie Int. Ed. Engl."},{"key":"B36","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1042\/CS20242825","article-title":"Heme oxygenase, biliverdin reductase, and bilirubin pathways regulate oxidative stress and insulin resistance: a focus on diabetes and therapeutics","volume":"139","author":"Lee","year":"2025","journal-title":"Clin. Science Lond. Engl."},{"key":"B37","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.redox.2016.06.006","article-title":"Quercetin inhibits LPS-induced adhesion molecule expression and oxidant production in human aortic endothelial cells by p38-mediated Nrf2 activation and antioxidant enzyme induction","volume":"9","author":"Li","year":"2016","journal-title":"Redox Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"106520","DOI":"10.1016\/j.intimp.2020.106520","article-title":"Physiological concentrations of bilirubin control inflammatory response by inhibiting NF-\u03baB and inflammasome activation","volume":"84","author":"Li","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.4049\/jimmunol.181.3.1887","article-title":"Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis","volume":"181","author":"Liu","year":"2008","journal-title":"J. Immunol. Baltim. Md"},{"key":"B40","doi-asserted-by":"publisher","first-page":"9886","DOI":"10.1038\/srep09886","article-title":"Bilirubin increases insulin sensitivity by regulating cholesterol metabolism, adipokines and PPAR\u03b3 levels","volume":"5","author":"Liu","year":"","journal-title":"Sci. Rep."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.2337\/db14-1391","article-title":"Unconjugated bilirubin mediates heme oxygenase-1-induced vascular benefits in diabetic mice","volume":"64","author":"Liu","year":"","journal-title":"Diabetes"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.19378\/j.issn.1003-9783.2020.11.001","article-title":"Dingxin recipe I prevents myocardial ischaemia\u2013reperfusion injury in rats by regulating the GSK3\u03b2\/Nrf2\/HO-1 pathway","volume":"31","author":"Liu","year":"2020","journal-title":"Tradit. Chin. Drug Res. Clin. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"26683","DOI":"10.1021\/acs.jafc.5c04774","article-title":"Ginsenoside Ro targets BCAT1\/2 to suppress ferroptosis: a novel therapeutic strategy for ischemic cardioprotection","volume":"73","author":"Liu","year":"2025","journal-title":"J. Agric. Food. Chem."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e92791","DOI":"10.1172\/jci.insight.92791","article-title":"Bilirubin suppresses Th17 immunity in colitis by upregulating CD39","volume":"2","author":"Longhi","year":"2017","journal-title":"JCI Insight"},{"key":"B45","doi-asserted-by":"publisher","first-page":"e0120259","DOI":"10.1371\/journal.pone.0120259","article-title":"Isorhamnetin attenuates atherosclerosis by inhibiting macrophage apoptosis via PI3K\/AKT activation and HO-1 induction","volume":"10","author":"Luo","year":"2015","journal-title":"PLoS One"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1007\/s10495-017-1381-3","article-title":"Dihydromyricetin protects human umbilical vein endothelial cells from injury through ERK and Akt mediated Nrf2\/HO-1 signaling pathway","volume":"22","author":"Luo","year":"2017","journal-title":"Apoptosis"},{"key":"B47","doi-asserted-by":"publisher","first-page":"73","DOI":"10.13412\/j.cnki.zyyl.2022.05.015","article-title":"Wenyang Tongmai Formula protects H9c2 cardiomyocytes against hypoxia\/reoxygenation-induced oxidative stress through the Nrf2\/HO-1 pathway [Article in Chinese]","volume":"38","author":"Ma","year":"2022","journal-title":"Pharmacol. Clin. Chin. Mater. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2952","DOI":"10.1021\/acs.molpharmaceut.7b00365","article-title":"Inhibition of human UGT1A1-Mediated bilirubin glucuronidation by polyphenolic acids impact safety of popular salvianolic acid A\/B-Containing drugs and herbal products","volume":"14","author":"Ma","year":"2017","journal-title":"Mol. Pharm."},{"key":"B49","doi-asserted-by":"publisher","first-page":"29251","DOI":"10.1074\/jbc.M109.037119","article-title":"Limited role for the bilirubin-biliverdin redox amplification cycle in the cellular antioxidant protection by biliverdin reductase","volume":"284","author":"Maghzal","year":"2009","journal-title":"J. Biol. Chem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"123120","DOI":"10.1016\/j.jns.2024.123120","article-title":"Serum direct bilirubin as a prognostic marker for short-term ischemic stroke morbidity and mortality: pooled analysis of cohort studies","volume":"463","author":"Mahadevan","year":"2024","journal-title":"J. Neurol. Sci."},{"key":"B51","doi-asserted-by":"publisher","first-page":"688","DOI":"10.5551\/jat.RV17035","article-title":"Bilirubin and endothelial function","volume":"26","author":"Maruhashi","year":"2019","journal-title":"J. Atheroscler. Thromb."},{"key":"B52","doi-asserted-by":"publisher","first-page":"E1029","DOI":"10.1152\/ajpendo.90241.2008","article-title":"Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes","volume":"296","author":"Ndisang","year":"2009","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"B53","doi-asserted-by":"publisher","first-page":"16712","DOI":"10.1016\/S0021-9258(19)89449-8","article-title":"Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation","volume":"269","author":"Neuzil","year":"1994","journal-title":"J. Biol. Chem."},{"key":"B54","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1080\/14756366.2021.2020773","article-title":"Pharmaceutical strategies for preventing toxicity and promoting antioxidant and anti-inflammatory actions of bilirubin","volume":"37","author":"Nocentini","year":"2022","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"B55","doi-asserted-by":"publisher","first-page":"118032","DOI":"10.1016\/j.lfs.2020.118032","article-title":"Bilirubin in metabolic syndrome and associated inflammatory diseases: new perspectives","volume":"257","author":"Nov\u00e1k","year":"2020","journal-title":"Life Sci."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1457010","DOI":"10.3389\/fimmu.2024.1457010","article-title":"The Nrf2-HO-1 system and inflammaging","volume":"15","author":"O'Rourke","year":"2024","journal-title":"Front. Immunol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"40","DOI":"10.5603\/KP.a2014.0117","article-title":"Low bilirubin levels are associated with coronary slow flow phenomenon","volume":"73","author":"Oz","year":"2015","journal-title":"Kardiol. Pol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"H1341","DOI":"10.1152\/ajpheart.00028.2018","article-title":"Mitochondrial bioenergetics and cardiolipin alterations in myocardial ischemia-reperfusion injury: implications for pharmacological cardioprotection","volume":"315","author":"Paradies","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"e3000410","DOI":"10.1371\/journal.pbio.3000410","article-title":"The ARRIVE guidelines 2.0: updated guidelines for reporting animal research","volume":"18","author":"Percie Du Sert","year":"2020","journal-title":"PLoS Biol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"20985","DOI":"10.1074\/jbc.M001038200","article-title":"A dynamic model for bilirubin binding to human serum albumin","volume":"275","author":"Petersen","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B61","doi-asserted-by":"publisher","first-page":"101023","DOI":"10.1016\/j.resplu.2025.101023","article-title":"Higher bilirubin on admission predicts better outcome in refractory cardiac arrest: a prague OHCA trial analysis focused on the antioxidant effect of bilirubin","volume":"25","author":"Pudil","year":"2025","journal-title":"Resusc. Plus."},{"key":"B62","doi-asserted-by":"publisher","first-page":"5800","DOI":"10.1111\/jocd.15240","article-title":"Bilirubin as a new antioxidant in melasma","volume":"21","author":"Rahimi","year":"2022","journal-title":"J. Cosmet. Dermatol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"107841","DOI":"10.1016\/j.intimp.2021.107841","article-title":"Ginsenoside Rg3 attenuates angiotensin II-induced myocardial hypertrophy through repressing NLRP3 inflammasome and oxidative stress via modulating SIRT1\/NF-\u03baB pathway","volume":"98","author":"Ren","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1152\/physrev.00011.2005","article-title":"Heme oxygenase-1\/carbon monoxide: from basic science to therapeutic applications","volume":"86","author":"Ryter","year":"2006","journal-title":"Physiol. Rev."},{"key":"B65","doi-asserted-by":"publisher","first-page":"5171","DOI":"10.1073\/pnas.0813132106","article-title":"Bilirubin and glutathione have complementary antioxidant and cytoprotective roles","volume":"106","author":"Sedlak","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B66","doi-asserted-by":"publisher","first-page":"e13920","DOI":"10.1097\/MD.0000000000013920","article-title":"Prognostic value of total bilirubin in patients with acute myocardial infarction: a meta-analysis","volume":"98","author":"Shen","year":"2019","journal-title":"Med. Baltim."},{"key":"B67","doi-asserted-by":"publisher","first-page":"197","DOI":"10.2220\/biomedres.45.197","article-title":"Quercetin protects human coronary artery endothelial cells against hypoxia\/reoxygenation-induced mitochondrial apoptosis via the Nrf2\/HO-1 axis","volume":"45","author":"Song","year":"2024","journal-title":"Biomed. Res."},{"key":"B68","doi-asserted-by":"publisher","first-page":"e18","DOI":"10.5546\/aap.2021.eng.e18","article-title":"Bilirubin: the toxic mechanisms of an antioxidant molecule","volume":"119","author":"Soto Conti","year":"2021","journal-title":"Arch. Argent. Pediatr."},{"key":"B69","doi-asserted-by":"publisher","first-page":"e0153427","DOI":"10.1371\/journal.pone.0153427","article-title":"Bilirubin binding to PPAR\u03b1 inhibits lipid accumulation","volume":"11","author":"Stec","year":"2016","journal-title":"PLoS One"},{"key":"B70","doi-asserted-by":"publisher","first-page":"945","DOI":"10.34067\/KID.0000062022","article-title":"Novel function for bilirubin as a metabolic signaling molecule: implications for kidney diseases","volume":"3","author":"Stec","year":"2022","journal-title":"Kidney360"},{"key":"B71","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.yjmcc.2004.10.006","article-title":"Administration of a CO-releasing molecule induces late preconditioning against myocardial infarction","volume":"38","author":"Stein","year":"2005","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1089\/ars.2004.6.841","article-title":"Antioxidant activities of bile pigments","volume":"6","author":"Stocker","year":"2004","journal-title":"Antioxid. Redox Signal."},{"key":"B73","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1161\/ATVBAHA.122.318086","article-title":"Association between serum bilirubin, lipid levels, and prevalence of femoral and carotid atherosclerosis: a population-based cross-sectional study","volume":"43","author":"Su","year":"2023","journal-title":"Arteriosclerosis, Thrombosis, Vascular Biology"},{"key":"B74","doi-asserted-by":"publisher","first-page":"e0223302","DOI":"10.1371\/journal.pone.0223302","article-title":"Bilirubin reduces visceral obesity and insulin resistance by suppression of inflammatory cytokines","volume":"14","author":"Takei","year":"2019","journal-title":"PLoS One"},{"key":"B75","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1097\/MCA.0000000000001546","article-title":"Bilirubin may mediate the anti-inflammatory effects of aerobic exercise habits: implications for the antiatherosclerotic effects of aerobic exercise","volume":"37","author":"Tani","year":"2026","journal-title":"Coron. Artery Dis."},{"key":"B76","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1073\/pnas.61.2.748","article-title":"The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase","volume":"61","author":"Tenhunen","year":"1968","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B77","doi-asserted-by":"publisher","first-page":"5483","DOI":"10.1007\/s12035-018-1440-y","article-title":"Bilirubin and ischemic stroke: rendering the current paradigm to better understand the protective effects of bilirubin","volume":"56","author":"Thakkar","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"8650","DOI":"10.3390\/ijms21228650","article-title":"The anti-inflammatory role of bilirubin on \u201cTwo-Hit\u201d sepsis animal model","volume":"21","author":"Tran","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B79","doi-asserted-by":"publisher","first-page":"R1186","DOI":"10.1152\/ajpregu.00729.2010","article-title":"Vasoactivity of the gasotransmitters hydrogen sulfide and carbon monoxide in the chicken ductus arteriosus","volume":"301","author":"van der Sterren","year":"2011","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1203\/00006450-200010000-00021","article-title":"Relaxant effects of carbon monoxide compared with nitric oxide in pulmonary and systemic vessels of newborn piglets","volume":"48","author":"Villamor","year":"2000","journal-title":"Pediatr. Res."},{"key":"B81","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1016\/j.jhep.2021.06.010","article-title":"Bilirubin: the yellow hormone?","volume":"75","author":"V\u00edtek","year":"2021","journal-title":"J. Hepatol."},{"key":"B82","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.molmed.2024.12.007","article-title":"Gut microbiota and bilirubin metabolism: unveiling new pathways in health and disease","volume":"31","author":"V\u00edtek","year":"2025","journal-title":"Trends Mol. Med."},{"key":"B83","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.molmed.2023.01.007","article-title":"The physiology of bilirubin: health and disease equilibrium","volume":"29","author":"V\u00edtek","year":"2023","journal-title":"Trends Mol. Med."},{"key":"B84","doi-asserted-by":"publisher","first-page":"e004820","DOI":"10.1161\/JAHA.116.004820","article-title":"Bilirubin prevents atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice by inhibiting endothelial VCAM-1 and ICAM-1 signaling","volume":"6","author":"Vogel","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"B85","doi-asserted-by":"publisher","first-page":"19","DOI":"10.3390\/ijms24043257","article-title":"Berberine alleviates doxorubicin-induced myocardial injury and fibrosis by eliminating oxidative stress and mitochondrial damage via promoting Nrf-2 pathway activation","volume":"24","author":"Wang","year":"","journal-title":"Int. J. Mol. Sci."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.13288\/j.11-2166\/r.2023.10.012","article-title":"Effects of Wutou Chishizhi Pill on oxidative stress and the Keap1\/Nrf2\/HO-1\/NQO1 pathway in rats with post-infarction myocardial hypertrophy [Article in Chinese]","volume":"64","author":"Wang","year":"","journal-title":"J. Tradit. Chin. Med."},{"key":"B87","doi-asserted-by":"publisher","first-page":"23","DOI":"10.3969\/j.issn.1674-070X.2025.01.004","article-title":"Effects of Conggan Zhixin Formula on myocardial Nrf2, HO-1, and iron-transport-related proteins in rats with myocardial ischaemia\u2013reperfusion injury [Article in Chinese]","volume":"45","author":"Wang","year":"2025","journal-title":"J. Hunan Univ. Chin. Med."},{"key":"B88","doi-asserted-by":"publisher","first-page":"e22505","DOI":"10.1096\/fj.202200543RRR","article-title":"Curcumin activates Nrf2\/HO-1 signaling to relieve diabetic cardiomyopathy injury by reducing ROS in vitro and in vivo","volume":"36","author":"Wu","year":"2022","journal-title":"FASEB Journal Official Publication Fed. Am. Soc. Exp. Biol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1136\/jnnp-2024-334408","article-title":"Total bilirubin modified the association between diabetes and stroke: a cross-sectional study from NHANES 2011\u20132016","volume":"96","author":"Xia","year":"2025","journal-title":"J. Neurology, Neurosurgery, Psychiatry"},{"key":"B90","doi-asserted-by":"publisher","first-page":"3295807","DOI":"10.1155\/2018\/3295807","article-title":"Curcumin inhibits acute vascular inflammation through the activation of heme Oxygenase-1. Oxidative med","volume":"2018","author":"Xiao","year":"2018","journal-title":"Cell. Longev."},{"key":"B91","doi-asserted-by":"publisher","first-page":"e70095","DOI":"10.1111\/cbdd.70095","article-title":"Tanshinone IIA ameliorates myocardial ischemia-reperfusion injury via activating HDAC1-Repressed Nrf2-xCT\/Gpx4\/HO-1 axis","volume":"105","author":"Yan","year":"2025","journal-title":"Chem. Biol. Drug Des."},{"key":"B92","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1248\/bpb.b18-00854","article-title":"Astragaloside IV regulates the PI3K\/Akt\/HO-1 signaling pathway and inhibits H9c2 Cardiomyocyte injury induced by hypoxia-reoxygenation","volume":"42","author":"Yang","year":"2019","journal-title":"Biol. Pharm. Bull."},{"key":"B93","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1097\/FJC.0000000000000769","article-title":"Berberine attenuates cholesterol accumulation in macrophage foam cells by suppressing AP-1 activity and activation of the Nrf2\/HO-1 pathway","volume":"75","author":"Yang","year":"2020","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.jconrel.2020.03.034","article-title":"Protective effects and mechanisms of bilirubin nanomedicine against acute pancreatitis","volume":"322","author":"Yao","year":"2020","journal-title":"J. Control. Release"},{"key":"B95","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.freeradbiomed.2024.09.042","article-title":"Biliverdin improved angiogenesis and suppressed apoptosis via PI3K\/Akt-mediated Nrf2 antioxidant system to promote ischemic flap survival","volume":"225","author":"Yao","year":"2024","journal-title":"Free Radic. Biol. Med."},{"key":"B96","doi-asserted-by":"publisher","first-page":"1514","DOI":"10.1016\/j.apsb.2025.02.003","article-title":"Dihydromyricetin mitigates abdominal aortic aneurysm via transcriptional and post-transcriptional regulation of heme oxygenase-1 in vascular smooth muscle cells","volume":"15","author":"Ye","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"B97","doi-asserted-by":"publisher","first-page":"100472","DOI":"10.1016\/j.jbo.2023.100472","article-title":"Indirect bilirubin impairs invasion of osteosarcoma cells via inhibiting the PI3K\/AKT\/MMP-2 signaling pathway by suppressing intracellular ROS","volume":"39","author":"Yuan","year":"2023","journal-title":"J. Bone Oncol."},{"key":"B98","doi-asserted-by":"publisher","first-page":"1490","DOI":"10.1248\/bpb.b17-00313","article-title":"A novel Danshensu-Tetramethylpyrazine conjugate DT-010 provides cardioprotection through the PGC-1\u03b1\/Nrf2\/HO-1 pathway","volume":"40","author":"Zhang","year":"2017","journal-title":"Biol. Pharm. Bull."},{"key":"B99","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/s00011-025-02049-w","article-title":"Bilirubin metabolism and its application in disease prevention: mechanisms and research advances","volume":"74","author":"Zhang","year":"2025","journal-title":"Inflamm. Res."},{"key":"B100","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.actbio.2020.12.047","article-title":"Polylysine-bilirubin conjugates maintain functional islets and promote M2 macrophage polarization","volume":"122","author":"Zhao","year":"2021","journal-title":"Acta Biomater."},{"key":"B101","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1186\/s12906-024-04492-4","article-title":"Ginsenoside Rg3 attenuates myocardial ischemia\/reperfusion-induced ferroptosis via the keap1\/Nrf2\/GPX4 signaling pathway","volume":"24","author":"Zhong","year":"2024","journal-title":"BMC Complement. Med. Ther."},{"key":"B102","doi-asserted-by":"publisher","first-page":"1907","DOI":"10.1124\/dmd.110.033829","article-title":"Bilirubin glucuronidation revisited: proper assay conditions to estimate enzyme kinetics with recombinant UGT1A1","volume":"38","author":"Zhou","year":"2010","journal-title":"Drug Metab. Dispos."},{"key":"B103","doi-asserted-by":"publisher","first-page":"114137","DOI":"10.1016\/j.biopha.2022.114137","article-title":"Sodium tanshinone IIA sulfonate protects against hyperhomocysteine-induced vascular endothelial injury via activation of NNMT\/SIRT1-mediated NRF2\/HO-1 and AKT\/MAPKs signaling in human umbilical vascular endothelial cells","volume":"158","author":"Zhou","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"B104","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.3390\/antiox10091352","article-title":"Serum bilirubin levels in overweight and Obese individuals: the importance of anti-inflammatory and antioxidant responses","volume":"10","author":"\u017diberna","year":"2021","journal-title":"Antioxidants"},{"key":"B105","doi-asserted-by":"publisher","first-page":"3964","DOI":"10.1007\/s12010-025-05211-6","article-title":"Astragaloside IV relieves mitochondrial oxidative stress damage and dysfunction in diabetic mice endothelial progenitor cells by regulating the GSK-3\u03b2\/Nrf2 axis","volume":"197","author":"Zou","year":"2025","journal-title":"Appl. Biochem. Biotechnol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1902935\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:30:19Z","timestamp":1789997419000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1902935\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":105,"alternative-id":["10.3389\/fphar.2026.1902935"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1902935","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]},"article-number":"1902935"}}