IngredientsXanthohumol (XN; chemical name: 3′-[3,3-dimethyl allyl]-2′,4′,4-trihydroxy-6′-methoxychalcone) is the principal prenylated chalcone of the hop plant. Its molecular formula is C21H22O5, and it is registered in PubChem under Compound ID 639665. Xanthohumol belongs to the flavonoid class of secondary metabolites and particularly to a subclass of chalcone precursors of flavonoids. The yellow compound — the name derives from the Greek xantho, meaning yellow — is found in high quantities in the lupulin glands of the hop plant's female cones.
Xanthohumol is a prenylated flavonoid derived from the female flowers of the hop plant (Humulus lupulus L.) of the family Cannabaceae. Xanthohumol (XN) is a natural chalcone found only in hops, which are the flowers from the hop plant Humulus lupulus that are almost exclusively used for beer production. In nature, XN exists ubiquitously within hops, with a content of 0.1%–1% (dry weight) in the female inflorescences. XN is secreted mainly as part of the hop resin and is also found in the trichomes on the underside of young leaves.
Xanthohumol is a prenylated chalconoid, biosynthesized by a type III polyketide synthase (PKS) and subsequent modifying enzymes, and is synthesized in the glandular trichomes of hop cones. L-Phenylalanine serves as the starting material, which is converted to cinnamic acid by the PLP-dependent phenylalanine ammonia lyase.
The dried hops contain 4–14% polyphenols, mainly phenolic acids, prenylated chalcones, flavonoids, catechins, and proanthocyanidins. Xanthohumol is the most abundant prenylated flavonoid, comprising 0.1–1% of dry weight in hops, and is also a constituent of beer — a major dietary source of prenylated flavonoids — where it has been found at concentrations up to 0.96 mg/L (1.95 μM).
Xanthohumol has been commonly isolated from hops through different extraction methods and used as a food supplement. The conventional XN isolation method was to use repeated chromatographic steps on silica gel using different solvents, and a recently established efficient way for the isolation and purification of XN from hops extract is by means of a high-speed counter-current chromatography method. Hop extracts for brewing are predominantly produced by extraction with supercritical carbon dioxide (CO2) or ethanol; however, xanthohumol can only be extracted in traces with CO2. When hops are extracted with pure ethanol or ethanol/water mixtures of high ethanol content (e.g., 90% by weight of ethanol or more), virtually all relevant hop constituents including xanthohumol can be extracted virtually completely.
A chemical synthesis method to synthesize XN using phloracetophenone (2′,4′,6′-trihydroxyacetophenone) as a precursor has been established; however, the process is complicated and the overall yield is relatively low. Thus, extraction, isolation, and purification from female inflorescences is still the main method to obtain XN. In supplemental contexts, XN is formulated as capsules, enriched beverages, and, more recently, in micellar preparations designed to overcome its poor water solubility. Hot trub and spent hops, by-products from beer brewing, can also serve as sources of xanthohumol.
Hop (Humulus lupulus L.) has been used since ancient times as a medicinal plant. Traditional medicinal indications included the treatment of anxiety and insomnia, mild pain reduction, and combating dyspepsia. Hops have long been used in the brewing industry as a preservative and flavoring agent to add bitterness and aroma to beer. In traditional Chinese medicine, hops are used to treat insomnia, restlessness, and dyspepsia.
Different biological activities have been attributed to prenylflavonoids from hops, such as prevention or treatment of (post-)menopausal "hot flashes" and osteoporosis; treatment of excitability and restlessness associated with tension headache; the ability to whet one's appetite and to improve digestion; relief for toothaches, earaches, and neuralgia. The female inflorescences of Humulus lupulus have also been used in traditional medicine mainly to treat sleep disturbances.
It is important to note that historical and traditional uses were directed at the hop plant as a whole, not at xanthohumol as an isolated compound. Since the 1990s, interest in health-promoting activities of XN specifically has increased constantly, and scientific investigations were initialized worldwide. The structure of XN was first identified by Verzele et al. in 1957; however, the beneficial pharmacological properties of XN were not appreciated until the 1990s, including its antioxidant, anti-inflammatory, antibacterial, antiviral, antifungal, and antiplasmodial activity.
Within the hop plant, xanthohumol is the dominant prenylated chalcone, but it co-occurs with several structurally related and biologically relevant compounds. The female flowers of hops (Humulus lupulus L.) contain the prenylated flavonoids xanthohumol (XN) and isoxanthohumol (IX). XN's isomer, 8-prenylnaringenin, is a phytoestrogen with strong estrogenic activity.
Xanthohumol itself is structurally characterized by a chalcone backbone bearing a prenyl (3,3-dimethylallyl) group, a methoxy group, and multiple hydroxyl groups. The regulation by XN of the Nrf2/NF-κB/mTOR/AKT pathways induces a strong antioxidant and anti-inflammatory effect, including the acceleration of autophagy through increased synthesis of Bcl-2 proteins, inhibition of the synthesis of VEGF responsible for angiogenesis, and phosphorylation of HKII (Hexokinase II).
The prenylated flavonoid XN has been observed to exert a variety of beneficial health-related effects, including anticarcinogenic activity in vitro and in vivo, primarily through its antioxidative properties, the inhibition of CYP450 enzymes, and, hence, prevention of pro-carcinogen activation, and the promotion of detoxifying processes. XN is a potent free-radical scavenger. Human studies have provided direct evidence: consumption of XN at 12 mg/day for 3 weeks protected DNA in white blood cells from oxidative damage as measured by the single cell gel electrophoresis. Blood levels of oxidized glutathione were significantly reduced by XN taken at a dose of 6 mg/day for 3 weeks. These findings suggest that XN administered in the form of a fortified non-alcoholic beverage is protective against DNA damage and oxidative stress in healthy individuals.
Xanthohumol has been shown to inhibit nuclear factor-κB (NF-κB) activation. NF-κB is a master regulator of inflammatory gene expression, and its inhibition by XN accounts for much of the compound's documented anti-inflammatory activity across multiple disease models. The multi-organ protective function of XH was described in a variety of chronic renal, cardiac, hepatic, and neural disorders and was attributed to its independent antioxidant and anti-inflammatory effect, mainly due to regulating AMPK, Nrf2, and NF-κB signaling. Indeed, XH can alleviate oxidative stress and inflammation by activating Nrf2 and inhibiting NF-κB.
XN, by modulating cell signaling pathways including ERK, AKT, NF-κB, AMPK, Wnt/β-catenin, and Notch signaling in cancer cells, inhibits tumor cell functions. Moreover, XN, by inducing apoptotic pathways — either intrinsic or extrinsic — promotes cancer cell death and arrests the cell cycle. Furthermore, XN inhibits metastasis, angiogenesis, cancer stemness, drug resistance, and cell respiration, resulting in the inhibition of tumor aggressiveness.
Xanthohumol significantly inhibited proliferation and NF-κB activation in pancreatic cancer cell lines. It also significantly suppressed the expression of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) at both the mRNA and protein levels.
Emerging evidence on the role of XN in cholesterol regulation has led to speculation that it may reduce risk factors associated with metabolic syndrome, including hypercholesterolemia and dyslipidemia. XN has been identified as an agonist of the farnesoid X receptor (FXR), which is involved in cholesterol and bile acid metabolism. Scientists concluded that several prenylflavonoids, particularly xanthohumol, clearly are a ligand — having a binding mechanism that promotes the activity of the Farnesoid X Receptor (FXR). FXR, in turn, is a master regulator of lipid and glucose metabolism.
It is not clear whether xanthohumol promotes reverse cholesterol transport (RCT); however, in vivo RCT experiments in a hamster model showed that xanthohumol significantly increased fecal appearance of the tracer derived from intraperitoneally injected [3H]-cholesterol-labeled macrophages. Cholesterol efflux capacity from macrophages was 1.5-fold higher in xanthohumol-fed hamsters compared with the control group. Protein expression and lecithin-cholesterol acyltransferase activity in the HDL fraction were significantly higher in xanthohumol-fed hamsters, suggesting that xanthohumol promoted HDL maturation.
AMPK stimulates hepatic fatty acid oxidation and peripheral insulin sensitivity and inhibits hepatic gluconeogenesis, de novo lipogenesis, and adipose tissue lipolysis by acting on several targets such as acetyl-CoA carboxylase (ACC), fatty acid synthase, SREBP1/2, AS160, TORC2, PPARγ, and other molecules. XN has been demonstrated to activate this pathway. In addition to its hepatoprotective effects, xanthohumol holds promise as a therapeutic agent for treating obesity, dysregulation of glucose metabolism, and other components of the metabolic syndrome including hepatic steatosis. Therapeutic xanthohumol application appears as a promising strategy, particularly in obese patients, to inhibit the development as well as the progression of non-alcoholic fatty liver disease.
Xanthohumol possesses potent antiplatelet activity, which may initially inhibit the PI3-kinase/Akt, p38 MAPK, and PLCγ2-PKC cascades, followed by inhibition of thromboxane A2 formation, thereby leading to inhibition of intracellular calcium and finally inhibition of platelet aggregation. This novel role of xanthohumol may represent high therapeutic potential for the treatment or prevention of cardiovascular diseases.
Xanthohumol faces significant pharmacokinetic challenges primarily due to its lipophilic nature. Due to its lipophilic nature, XN is poorly soluble in water and barely absorbed from the gastrointestinal tract, which greatly limits its therapeutic potential. This low solubility restricts the dissolution of the compound in the aqueous environment of the digestive system, leading to suboptimal absorption through passive diffusion.
The bioavailability of this chalcone after administration to rats at doses of 40, 100, and 200 mg/kg body weight was 1.16%, 0.96%, and 0.53%, respectively, which may be the result of significantly limited absorption in the small intestine and the rapid metabolism of xanthohumol by microorganisms in the colon.
Following ingestion, XN undergoes extensive biotransformation in the liver and intestines, which limits its presence in the bloodstream. Phase I and Phase II metabolic processes, including oxidation, reduction, and conjugation reactions (such as glucuronidation and sulfation), lead to the formation of various metabolites, including isoxanthohumol and 8-prenylnaringenin.
Bolca et al. reported that the mean recovery of free and conjugated XN was 0.32% from the 24-hour urine of post-menopausal women after 5 days of daily intake of 1.38 mg XN. These data show that XN is absorbed and metabolized in vivo, but the bioavailability of XN has not yet been established in quantitative terms.
According to recent studies, enhancing the solubility of XN is a critical area for future research. Approaches such as the use of cyclodextrin complexes, micellar formulations, or nano-encapsulation have shown promise in improving the solubility and overall bioavailability of XN in experimental models. Human clinical data confirm this effect: bioavailability was mainly influenced by micellation and was approximately 9-fold higher after intake of micellar xanthohumol than after intake of the native form, irrespective of the dose. Recent advances in micellar formulations have improved XN's systemic bioavailability and thus its translational feasibility.
Evidence level: Preliminary human evidence from small studies.
The most direct human evidence for XN's antioxidant activity comes from a study using a xanthohumol-enriched non-alcoholic beverage. Consumption of XN at 12 mg/day for 3 weeks protected DNA in white blood cells from oxidative damage as measured by single cell gel electrophoresis. Blood levels of oxidized glutathione were significantly reduced by XN taken at a dose of 6 mg/day for 3 weeks. These findings suggest that XN administered in the form of a fortified non-alcoholic beverage is protective against DNA damage and oxidative stress in healthy individuals. No treatment-related adverse effects were reported or observed in this study. Antioxidant activity, including inhibition of LDL oxidation in vitro and DNA protective effects in humans, have also been demonstrated. These findings are encouraging but come from small populations; larger confirmatory trials have not yet been published.
Evidence level: Primarily preclinical (in vitro and animal); limited human data.
Human subject studies demonstrate that XN is safe and well tolerated, with observed reductions in oxidative DNA damage and inflammatory cytokine release. The mechanistic basis, described above, involves inhibition of NF-κB and activation of Nrf2. Most evidence for clinically meaningful anti-inflammatory effects in specific diseases remains confined to cell culture and animal studies. The Phase I XMaS trial assessed inflammatory biomarkers as secondary endpoints; the effects of XN on inflammatory biomarkers, platelet function, the microbiota, and multi-omics biomarkers were measured, with a Phase II Crohn's disease trial ongoing.
Evidence level: Extensive preclinical (in vitro and animal); no completed human clinical trials assessing efficacy.
Xanthohumol has been shown to inhibit the growth of different types of human cancer cells, including breast, colon, hepatocellular, ovarian, pancreatic, and prostate cancer cells as well as leukemia cells. In addition, xanthohumol has been shown to induce both caspase-dependent and caspase-independent apoptosis and to inhibit invasion and angiogenesis.
In oncology, XN demonstrates broad-spectrum anticancer activity in preclinical models by inhibiting proliferation; inducing cell cycle arrest and apoptosis; suppressing epithelial–mesenchymal transition, angiogenesis, and metastasis; and restoring chemosensitivity in resistant cancers, including breast, lung, gastric, liver, and head-and-neck carcinomas.
In hepatocellular carcinoma cell lines specifically, XN concentrations of 5 μM and above significantly reduced cell viability, colony-forming ability, and confluency of all four HCC cell lines studied. Growth suppression due to apoptosis was evidenced by increased expression of pro-apoptotic and reduced expression of anti-apoptotic proteins. XN treatment inhibited the Notch signaling pathway as evidenced by the decrease in the expression of Notch1 and HES-1 proteins.
In vitro, XN inhibits proliferation of breast, colon, hepatocellular, ovarian, pancreatic, prostate, and medullary thyroid cancer cell lines. Despite the breadth of preclinical evidence, no human clinical trials demonstrating anticancer efficacy have been completed. The evidence base currently does not permit conclusions about cancer prevention or treatment in humans.
Evidence level: In vitro and animal model data only; no published human clinical trials in this context.
The scientific evidence available about the beneficial effects of xanthohumol in the prevention and/or treatment of obesity, dyslipidemia, insulin resistance, and fatty liver — important components of metabolic syndrome — has been observed in vitro and in animal models; there are no published clinical trials in this context yet.
In a key animal study, xanthohumol was tested for efficacy on biomarkers of metabolic syndrome in 4-week-old Zucker fa/fa rats, a rodent model of obesity. Rats received daily oral doses of xanthohumol at 0, 1.86, 5.64, and 16.9 mg/kg body weight for 6 weeks. All rats were maintained on a high-fat (60% kcal) AIN-93G diet for 3 weeks to induce severe obesity, followed by a normal AIN-93G (15% kcal fat) diet for the last 3 weeks of the study.
It is notable that in addition to its hepatoprotective effects, xanthohumol also holds promise as a therapeutic agent for treating obesity, dysregulation of glucose metabolism, and other components of the metabolic syndrome including hepatic steatosis. However, these conclusions are drawn from preclinical models only.
Evidence level: Animal and in vitro data; one bioavailability human RCT with negative acute findings on hemodynamic parameters.
Xanthohumol is suggested to be antiatherogenic since it reportedly increases high-density lipoprotein (HDL) cholesterol levels. Mechanistic studies in animal models support the idea of reverse cholesterol transport enhancement, reduced platelet aggregation, and improved lipid profiles. However, a human randomized controlled crossover bioactivity trial produced a null finding on acute hemodynamic measures: a randomized placebo-controlled crossover bioactivity trial showed no acute effects of 172 mg micellar xanthohumol on resting energy expenditure, blood pressure, or heart rate. Longer-term and larger cardiovascular endpoint trials in humans have not been reported.
Evidence level: Preclinical (cell and animal); no controlled human trials.
Xanthohumol inhibits several critical pathophysiological steps during the development and course of chronic liver disease, including the activation and pro-fibrogenic genotype of hepatic stellate cells. The various mechanisms of action and molecular targets of the beneficial xanthohumol effects have been described, and the potential use of xanthohumol or a xanthohumol-enriched hop extract as a therapeutic agent to combat the progression of chronic liver disease has been discussed.
XN shows beneficial effects in preclinical models of hepatic steatosis and fibrosis. The AMPK/Nrf2/NF-κB signaling axis mediates much of this hepatoprotection, as detailed in the mechanisms section. Human evidence remains absent; the planned XMaS Phase II trial in Crohn's disease patients will provide some relevant inflammatory and gut-barrier data that may indirectly inform liver inflammation research.
Evidence level: Preclinical cell culture and animal models; no completed human clinical trials for neurodegenerative conditions.
The role of XN in the prevention of neurodegenerative diseases encompasses its effect at a molecular level, including signal transduction and metabolism. Research has addressed XN's mechanism of action, potential effects, and experimental and clinical studies on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).
In a cellular AD model, the prenylflavonoid xanthohumol from the Common Hop was assessed for therapeutic potential in murine neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (N2a/APP). ELISA and Western-blot analysis revealed that xanthohumol inhibited Aβ accumulation and APP processing, and ameliorated tau hyperphosphorylation via PP2A, GSK3β pathways in N2a/APP cells.
XN demonstrates broad neuroprotective effects across acute neurological injuries, chronic neurodegenerative diseases, and psychiatric conditions in preclinical settings. Research has explored xanthohumol's potential anti-inflammatory and neuroprotective properties, though most studies remain preliminary. No human data on neurodegenerative endpoints are available as of the time of writing.
Evidence level: In vitro only.
Beyond cancer, XN exhibits multi-organ protective bioactivities through antioxidative, antimicrobial, antiviral, and anti-inflammatory activities. Studies have shown that XN acts in an anti-microbial and anti-viral capacity. These findings are from laboratory experiments and have not been translated into clinical trials. XN has been found to have various biological effects, including anti-microbial, anti-viral, and immunomodulatory activities, but all such evidence is preclinical in nature.
Evidence level: Phase I safety established; Phase II efficacy trial ongoing.
Xanthohumol (XN), a bioactive flavonoid from Humulus lupulus with anti-inflammatory properties, has potential benefits for patients with Crohn's disease (CD). A placebo-controlled phase I clinical trial demonstrated the safety and tolerability of 24 mg XN daily for 8 weeks. A phase II clinical trial is aimed at evaluating the safety and tolerability of the same dose of XN in adults with clinically active CD. Additional aims will assess the impact of XN on inflammatory biomarkers, platelet function, CD clinical activity, and stool microbial composition.
The following dosages appear in the published literature reviewed and are reported here strictly as recorded in those sources.
The dose of 24 mg/day aligns with the highest dose for which preliminary evidence of safety, tolerability, and biological effects had been established at the time of the XMaS trial design.
Animal and human studies of xanthohumol have revealed its diverse biological features, including anti-inflammatory, anti-cancer, anti-oxidant, and anti-diabetic activities, as well as other related properties.
A triple-masked, placebo-controlled phase I clinical trial was conducted to examine the safety and tolerability of xanthohumol. Thirty healthy volunteers were randomized to 24 mg/day xanthohumol (99.8% pure) or placebo for eight weeks. Comprehensive metabolic panels, complete blood counts, body weight, vital signs, and health-related quality of life questionnaires were assessed every two weeks. Participants were interviewed for adverse events throughout the trial. There were no withdrawals due to adverse events. There were no clinically relevant, between-group differences in laboratory biomarkers, body weight, vital signs, or health-related quality of life.
The phase I clinical trial demonstrated the safety and tolerability of 24 mg/day of XN over 8 weeks in healthy adults, corroborated by previous animal and human pharmacokinetics models indicating XN is safe to consume as an isolated constituent. Furthermore, the US Food and Drug Administration (FDA) classifies both hops and hops oil as "Generally Recognized as Safe" (GRAS).
In preclinical toxicity assessments, feeding female mice with xanthohumol for 3 weeks, resulting in a daily dose of approximately 1000 mg xanthohumol/kg body weight, showed that histopathological examination of the liver, kidney, colon, lung, heart, spleen, and thymus revealed no signs of toxicity, and biochemical serum analysis confirmed normal organ function.
A well-documented safety concern relates not to XN itself but to its metabolites. Xanthohumol's use raises concerns as gut microbiota and the host's hepatic cytochrome P450 enzymes metabolize it into the most potent phytoestrogen known, 8-prenylnaringenin (8-PN). In the host, 8-PN acts as a strong agonist for estrogen receptors located in cells throughout the body, which could increase one's risk of developing hormone-dependent cancers. Thus, its estrogenic activity is of concern, and additional studies to assess the safety of 8-PN in long-term supplementation are needed.
Despite positive effects, the use of XN raises concerns, as it was shown both in vitro and in vivo that XN is metabolized into 8-prenylnaringenin (8-PN), the most potent phytoestrogen currently known. Researchers have investigated non-estrogenic XN derivatives (dihydroxanthohumol and tetrahydroxanthohumol) as alternatives: the XN derivatives dihydroxanthohumol (DXN) and tetrahydroxanthohumol (TXN) are not metabolized into 8-PN, and they show higher tissue concentrations in vivo compared with XN when orally administered to mice at the same dose. DXN and TXN possess improved anti-proliferative activity compared with XN in colon and hepatocellular carcinoma cell lines.
Although XN exhibits low toxicity at moderate doses, higher concentrations could potentially pose risks, as suggested by its structural similarity to other flavonoids, which can influence estrogenic and anti-estrogenic activity in some tissues. Prolonged high-dose exposure might also interact with cytochrome P450 enzymes, affecting drug metabolism pathways and leading to potential drug interactions. This has not been characterized in controlled human pharmacological interaction studies to date.
Further studies are needed to determine the safety threshold and to explore any long-term metabolic or hormonal effects of XN supplementation. Individuals with pre-existing liver conditions or those on medications metabolized by the liver should exercise caution with XN supplementation.
Only a few studies have evaluated the safety of this compound for human consumption. All completed human trials have been short-term (up to 8 weeks) and at modest doses (up to 24 mg/day in controlled settings, or 86–172 mg in single-dose bioavailability studies). Data on long-term supplementation at higher doses in humans are absent. Although xanthohumol has been formally evaluated in a pharmacokinetics study in humans, no previous studies had prospectively evaluated the safety and tolerability of xanthohumol, as an isolated constituent, in human subjects prior to the XMaS trial.
Health conditions that Xanthohumol may help support.
Xanthohumol is the principal prenylated chalcone in hops (Humulus lupulus). It is a phytoestrogen that can be metabolized to isoxanthohumol and further to 8-prenylnaringenin (the most potent known phytoestrogen) by gut bacteria. It binds estrogen receptors and modulates estrogen-dependent gene expression in vitro.
Body systems that Xanthohumol may help support.
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