{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T05:53:49Z","timestamp":1788587629667,"version":"build-2803163510"},"reference-count":121,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015326","name":"the National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL149762"],"award-info":[{"award-number":["R01HL149762"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015326","name":"the National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR073172"],"award-info":[{"award-number":["R01AR073172"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015326","name":"the National Institutes of Health","doi-asserted-by":"publisher","award":["1R21AR083066"],"award-info":[{"award-number":["1R21AR083066"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"publisher","award":["HT9425-23-10008"],"award-info":[{"award-number":["HT9425-23-10008"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the University of South Carolina School of Medicine Bridge Funding"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Xanthohumol (XN), a prenylated chalcone flavonoid derived from hops (Humulus lupulus), is increasingly recognized as a highly pleiotropic natural compound. Objective: We aimed to structure XN\u2019s mechanistic hierarchy with emerging translational relevance across disease areas. Methods: We performed a comprehensive and integrative literature review of XN for its biological and translational effects across cancer, metabolic, neurological, cardiovascular, hepatic, renal, and dermatological disorders. Results: Mechanistically, XN exerts diverse bioactivities by inhibiting major pro-oncogenic and pro-inflammatory pathways, such as NF-\u03baB, PI3K\/Akt\/mTOR, STAT3, HIF-1\u03b1, and selective MAPK cascades, while activating cytoprotective signaling, such as the Nrf2\/ARE and AMPK pathways. Through these coordinated actions, XN modulates redox homeostasis, mitochondrial integrity, apoptosis, autophagy, ferroptosis, and inflammatory responses. In oncology, XN demonstrates broad-spectrum anticancer activity in preclinical models by inhibiting proliferation; inducing cell cycle arrest and apoptosis; suppressing epithelial\u2013mesenchymal transition, angiogenesis, and metastasis; and restoring chemosensitivity in resistant cancers, including breast, lung, gastric, liver, and head-and-neck carcinomas. Beyond cancer, XN exhibits multi-organ protective bioactivities through antioxidative, antimicrobial, antiviral, and anti-inflammatory activities; inhibition of ferroptosis and excitotoxicity; and preservation of mitochondrial integrity. It shows beneficial effects in preclinical models of Parkinson\u2019s disease, Alzheimer\u2019s disease, hepatic steatosis and fibrosis, renal ischemia\u2013reperfusion injury, cardiovascular dysfunction, skin photoaging, and atopic dermatitis. Human subject studies demonstrate that XN is safe and well tolerated, with observed reductions in oxidative DNA damage and inflammatory cytokine release. Recent advances in micellar formulations have improved XN\u2019s systemic bioavailability and thus its translational feasibility. Conclusions: In summary, XN is a safe, multifunctional natural compound with strong potential for modulating disease-relevant biological pathways associated with cancer, neurodegenerative diseases, metabolic disorders, and inflammatory skin conditions. Continued efforts to enhance its bioavailability and conduct rigorous clinical trials are essential to fully establish its clinical relevance in patient populations.<\/jats:p>","DOI":"10.3390\/nu18030520","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T12:46:11Z","timestamp":1770122771000},"page":"520","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Xanthohumol: Mechanistic Actions and Emerging Evidence as a Multi-Target Natural Nutraceutical"],"prefix":"10.3390","volume":"18","author":[{"given":"Mackenzie","family":"Azuero","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0815-3568","authenticated-orcid":false,"given":"Camilla F.","family":"Wenceslau","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29209, USA"},{"name":"Department of Biomedical Engineering, College of Engineering and Computing, University of South Carolina, Columbia, SC 29208, USA"},{"name":"The Cardiovascular Translational Research Center, School of Medicine, University of South Carolina, Columbia, SC 29209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-8988","authenticated-orcid":false,"given":"Wenbin","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29209, USA"},{"name":"Department of Biomedical Engineering, College of Engineering and Computing, University of South Carolina, Columbia, SC 29208, USA"},{"name":"The Cardiovascular Translational Research Center, School of Medicine, University of South Carolina, Columbia, SC 29209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1186\/s13063-020-04769-2","article-title":"Xanthohumol microbiome and signature in healthy adults (the XMaS trial): A phase I triple-masked, placebo-controlled clinical trial","volume":"21","author":"Bradley","year":"2020","journal-title":"Trials"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5431","DOI":"10.2147\/DDDT.S282206","article-title":"Xanthohumol Inhibits TGF-beta1-Induced Cardiac Fibroblasts Activation via Mediating PTEN\/Akt\/mTOR Signaling Pathway","volume":"14","author":"Jiang","year":"2020","journal-title":"Drug Des. 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