{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T05:01:53Z","timestamp":1789794113208,"version":"4.0.1"},"reference-count":451,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Hyperforin, a polyprenylated acylphloroglucinol and major bioactive constituent of Hypericum perforatum L. (H. perforatum, St. John\u2019s Wort), has attracted considerable interest because of its pleiotropic pharmacological properties. Although historically investigated primarily for its contribution to the antidepressant activity of H. perforatum, experimental studies have identified broader neuroprotective, anti-inflammatory, antioxidant, immunomodulatory, antimicrobial, metabolic, anticancer, and tissue-regenerative actions. However, the evidence remains heterogeneous, and an important distinction exists between findings obtained with purified hyperforin and those derived from multicomponent H. perforatum preparations. Unlike previous reviews that have primarily summarized the pharmacological activities of hyperforin, the present review adopts a translational evidence framework that distinguishes purified hyperforin from multicomponent H. perforatum preparations and evaluates the maturity of evidence from molecular mechanisms and preclinical models through pharmacokinetics, human studies, safety, and clinical development. A comprehensive narrative review was conducted according to the Scale for the Assessment of Narrative Review Articles (SANRA) recommendations. PubMed\/MEDLINE, Scopus, Web of Science, Embase, and Google Scholar were searched from database inception through 25 July 2026. Mechanistic, in vitro, animal, translational, pharmacokinetic, and clinical studies, together with relevant systematic reviews and meta-analyses, were critically synthesized according to intervention type, disease-specific evidence, pharmacokinetic and formulation characteristics, safety, and translational relevance. Hyperforin acts as a pleiotropic signaling modulator affecting interconnected pathways involved in neurotransmission and neuroplasticity, inflammatory and redox regulation, mitochondrial and cellular homeostasis, immune function, and metabolism. Extensive cellular and animal evidence supports biological activity across neuropsychiatric, neurodegenerative, inflammatory, immune-mediated, cardiometabolic, oncological, gastrointestinal, infectious, dermatological, and other chronic disease settings. Nevertheless, evidence maturity differs markedly among indications. The strongest human evidence concerns standardized hyperforin-containing H. perforatum preparations for mild-to-moderate depression, whereas most other applications remain preliminary or predominantly preclinical. Adequately powered randomized controlled trials of purified hyperforin are lacking, preventing attribution of the clinical effects of H. perforatum preparations specifically to hyperforin. Translation is further constrained by poor aqueous solubility, chemical instability, variable bioavailability and formulation composition, limited compound-specific pharmacokinetic data, and clinically important herb\u2013drug interactions, particularly through PXR-mediated induction of CYP3A4 and P-glycoprotein. Hyperforin is a pharmacologically promising multifunctional natural compound, but its experimental activity currently exceeds the strength of compound-specific clinical evidence. Future research should prioritize chemically defined and preferably purified formulations, rigorous pharmacokinetic and dose-finding studies, biomarker-supported target-engagement assessment, and adequately powered randomized controlled trials, together with long-term safety, interaction, standardization, and regulatory evaluation. Demonstrating predictable human exposure, biologically relevant target engagement, clinically meaningful efficacy, and an acceptable long-term safety profile will be essential for determining whether hyperforin can progress from experimental promise to evidence-based therapeutic application.<\/jats:p>","DOI":"10.3390\/cimb48090937","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:05:26Z","timestamp":1789391126000},"page":"937","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hyperforin as a Multifunctional Specialized Metabolite of Natural Origin for Chronic Diseases: From Molecular Mechanisms to Clinical Translation"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0928-9639","authenticated-orcid":false,"given":"Efthymios","family":"Poulios","sequence":"first","affiliation":[{"name":"Department of Food Science and Nutrition, University of the Aegean, 81400 Lemnos, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6408-6128","authenticated-orcid":false,"given":"Sousana K.","family":"Papadopoulou","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences and Dietetics, International Hellenic University, 57001 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Exakousti-Petroula","family":"Angelakou","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, University of the Aegean, 81400 Lemnos, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerasimos","family":"Tsourouflis","sequence":"additional","affiliation":[{"name":"2nd Propaedeutic Department of Surgery, Laiko General Hospital of Athens, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aspasia","family":"Serdari","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2878-4831","authenticated-orcid":false,"given":"Constantinos","family":"Giaginis","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, University of the Aegean, 81400 Lemnos, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref_1","first-page":"1045","article-title":"Hypericum perforatum: Traditional Uses, Clinical Trials, and Drug Interactions","volume":"25","author":"Nobakht","year":"2022","journal-title":"Iran. 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