IngredientsDiosmetin (also known as 4′-methylluteolin, luteolin 4′-methyl ether, or 5,7,3′-trihydroxy-4′-methoxyflavone) is a natural methylated flavone. Its molecular formula is C16H12O6 and its molecular weight is 300 g/mol. The diosmetin structure includes a 15-carbon skeleton, which consists of two phenyl rings (A and B) and a heterocyclic ring (C). Diosmetin has three hydroxyl groups at the 5, 7, and 3′ positions. Being a flavone, the molecule has a C2–C3 double bond and a 4-carbonyl group but lacks the C3 hydroxyl group at ring C.
Diosmetin is the aglycone part of the flavonoid glycoside diosmin and occurs naturally in citrus fruit. The relationship between diosmin and diosmetin is pharmacologically important: following oral administration, diosmin is not directly absorbed but must first be hydrolyzed into its aglycone, diosmetin, which is then absorbed into the systemic circulation. Diosmetin is an aglycone of diosmin, a drug with a protective effect on blood vessels, used in the treatment of venous insufficiency.
Diosmetin is a natural flavonoid compound belonging to the flavone subclass of flavonoids. It is found in various plants and fruits including citrus fruits, such as oranges and lemons, and some herbs and various vegetables. Citrus limon L. (lemon) and other natural sources of diosmetin, such as Rosmarinus officinalis (rosemary) and Olea europaea (olive), have been shown to have therapeutic potential. Approximately 27 mg/kg of diosmetin is present in the leaves of Olea europaea L., while Citrus lemon contains high levels of all flavonoids (80–95%), with 32 ± 4.95 mg/100 mL of diosmetin.
Diosmetin is a naturally occurring flavonoid found in large quantities in Schizonepeta tenuifolia Briq. Diosmetin is primarily found in citrus fruits, beans, and other plants. Additional botanical sources documented in the peer-reviewed literature include Dracocephalum peregrinum L. — a traditional Kazakh medicinal plant — from which diosmetin has been isolated as the principal flavonoid.
Diosmetin is defined as one of the active concomitant flavonoids present in the micronized purified flavonoid fraction (MPFF) along with diosmin, and it contributes to the pharmacological effects of MPFF in improving venous tone and exhibiting anti-inflammatory properties. As a standalone ingredient, diosmetin is available as a purified powder or in oral capsule and tablet forms. Research has also examined cyclodextrin inclusion complexes and micronized formulations to improve its characteristically poor water solubility and oral bioavailability. The use of pure diosmetin is limited due to its low bioavailability.
Diosmetin as a purified compound is a product of modern phytochemistry and does not have a documented traditional use as an isolated molecule. However, the plants that serve as its principal sources have long, well-established histories in Mediterranean, European, Chinese, and Kazakh traditional medicine systems.
Citrus species — the primary botanical reservoir of diosmetin and its glycoside diosmin — have been cultivated and used medicinally in the Mediterranean basin, the Middle East, and Asia for millennia. The peel, juice, and flowers of Citrus limon and other species were employed in traditional Greco-Roman, Arabic, and Ayurvedic medicine for digestive complaints, febrile conditions, wound healing, and vascular ailments. Similarly, Rosmarinus officinalis (rosemary) has a continuous record of use in Mediterranean folk medicine for circulatory complaints, anti-inflammatory purposes, and as a culinary herb since at least classical antiquity.
Dracocephalum peregrinum L. is a traditional Kazakh medicine with documented expectorant, anti-cough, and to some degree, anti-asthmatic effects. Diosmetin, a natural flavonoid found in traditional Chinese herbs, is the main flavonoid in D. peregrinum L. and has been used in various medicinal products because of its anticancer, antimicrobial, antioxidant, estrogenic, and anti-inflammatory effects.
In Europe, diosmin — the glycoside from which diosmetin is derived upon digestion — has a well-documented history of clinical pharmaceutical use. In Europe, diosmin has been widely used for a long time as a phlebotonic and vascular protector for oral use in different types of pharmaceutical and nutritional products. This phlebotonic tradition, rooted in the mid-twentieth-century development of standardized flavonoid preparations from citrus, underpins much of the contemporary scientific interest in diosmetin specifically.
It must be noted that the available ethnobotanical literature does not record diosmetin by name in traditional texts, since the isolated aglycone was identified only through modern phytochemical analysis. Traditional use refers to the parent plants and their whole-plant preparations, with diosmetin being one of the bioactive constituents responsible for observed effects.
Flavonoids exhibit various pharmacological activities such as antioxidant, anti-inflammatory, anti-allergic, antibacterial, oestrogenic, cytotoxic antitumoural, hepatoprotective, antithrombotic and antiviral activity. Diosmetin's activities arise from its specific hydroxylation and methoxylation pattern. The presence of a methoxy group at the 4′ position (distinguishing it from its close structural relative luteolin, which carries a hydroxyl at that position) confers distinct receptor-binding properties, particularly at estrogen receptors, and alters its metabolic fate.
Studies have demonstrated that diosmetin can slow down the progression of inflammation by inhibiting the production of inflammatory mediators through modulating related pathways, predominantly the nuclear factor-κB (NF-κB) signaling pathway.
At the cellular level, multiple pathways have been delineated in preclinical models:
Diosmetin promotes strong cellular antioxidant activity in human monocytes by preventing the generation of intracellular ROS and the formation of malondialdehyde (MDA), and by increasing the effects of the intracellular antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Diosmetin is well documented to enhance antioxidant activity by inhibiting ROS and increasing intracellular antioxidant status. The compound also activates the NRF2 (nuclear factor erythroid-2-related factor 2) pathway, which is a master regulator of cellular antioxidant defense. Diosmetin exerts cytoprotective effects against lipopolysaccharide-induced acute lung injury through inhibition of the NLRP3 inflammasome and the activation of NRF2.
Research has evaluated the anticancer potential of diosmetin, shedding light on its mechanisms of action such as cell cycle regulation, apoptosis via both intrinsic and extrinsic pathways, autophagy, and tumour progression and metastasis.
In osteosarcoma cell studies, diosmetin significantly suppressed cell proliferation in both Saos-2 and U2OS cell lines and caused an obvious cell cycle arrest which mainly occurred in the G2/M phase. Diosmetin could remarkably promote cell apoptosis with reduced anti-apoptotic protein Bcl-xL while elevating pro-apoptotic proteins cleaved Caspase-3, cleaved-PARP, and BAX.
Data have shown Ca2+ channel antagonism, potassium channel activation, and antimuscarinic receptor-linked vasodilatory effects of diosmetin, which demonstrate its antihypertensive potential. Diosmetin has been emphasized to exhibit various properties, including estrogenic, antioxidant, anti-inflammatory, antitumor, anti-apoptotic, and hypolipidemic activities.
Diosmetin is reported to exhibit anticancer, antimicrobial, antioxidant, oestrogenic, and anti-inflammatory activities. Diosmetin acts as a phytoestrogen, showing selective activity at estrogen receptor subtypes. Research has demonstrated that CYP1 enzymes (CYP1A1, CYP1A2, CYP1B1) are involved in diosmetin's bioactivation, and the compound has been studied for its CYP1-mediated anticancer effects in estrogen receptor-positive cancer cell lines.
Under natural conditions, the majority of flavonoids exist in the form of glycosides (i.e., linked with various sugar moieties) which are poorly absorbed by the human gut. In order to become bioactive in the human body, these compounds need to be hydrolyzed to their aglycone form by enzymes found in the intestinal flora. Orally administered diosmin is not absorbed through the mucosa of the small intestine, but is hydrolyzed to its aglycone diosmetin only by rhamnosidases produced by enterobacteria as it enters the cecum and colon, the sites of absorption.
At the level of sensitivity of standard analytical methods, no parent diosmin compound is present in plasma but only its aglycone, diosmetin. Analysis of pharmacokinetic parameters shows that the drug is rapidly absorbed. Diosmetin presents a long plasma elimination half-life ranging from 26 to 43 hours. Urinary elimination for both diosmin and its aglycone diosmetin is absent, while minor metabolites are eliminated in the urine, mainly as glucuronic acid conjugates.
Diosmin is rapidly hydrolyzed in the intestine to its aglycone, diosmetin, which is further metabolized to conjugates. The principal glucuronide metabolites include diosmetin-3-O-glucuronide, diosmetin-7-O-glucuronide, and diosmetin-3,7-O-glucuronide, detectable in human plasma and urine.
The use of pure diosmetin is limited due to its low bioavailability. Studies have explored various formulation strategies to overcome this. A cross-over clinical study assessed the pharmacokinetic profile of µSmin® Plus, a micronized diosmin flavonoid complex standardized in diosmin and formulated with a buffering agent, compared to unformulated micronized diosmin (reference), in 16 healthy volunteers. The tested formulation showed higher plasma concentrations of diosmetin in comparison to those obtained after the administration of unformulated micronized diosmin. The relative bioavailability was 9.4 times greater for the tested formulation than for micronized diosmin.
Diosmetin-3-O-β-D-glucuronide induced anti-inflammatory and antioxidant responses, with the maximal effect being reached at 2700 pg/mL and corresponding to the peak plasma concentration estimated after the oral intake of 600 mg of diosmin, the daily dose usually recommended for the treatment of chronic venous disease (CVD). These ex vivo findings suggest a protective role of diosmetin-3-O-β-D-glucuronide against inflammatory and oxidative stress affecting the vascular system in CVD pathophysiology.
Evidence grade: Preclinical only (in vitro and animal models); no completed human randomized controlled trials for diosmetin as an isolated compound.
Accumulating evidence so far suggests a very important role for diosmetin in the treatment of various inflammatory disorders and suggests it is a candidate worthy of in-depth investigation. The anti-inflammatory evidence base consists primarily of cell culture and rodent models. The anti-inflammatory properties of diosmetin have been discussed in cellular and animal models of various inflammatory diseases.
In a rheumatoid arthritis model, diosmetin inhibited TNF-α-induced proliferation increase in MH7A cells in a dose-dependent manner. Diosmetin treatment resulted in an increase in apoptotic rates and a reduction in TNF-α-induced production of IL-1β, IL-6, IL-8, and MMP-1. This was in vitro work using a human-derived cell line; no corresponding clinical trial in RA patients has been completed with diosmetin alone.
For atopic dermatitis, diosmetin and its glycoside diosmin greatly reduced the AD-like lesions in DNCB-induced murine models. Diosmetin improved the AD-like lesions by inhibiting transepidermal water loss (TEWL) and reduced the IgE and IL-4 expression in RBL-2H3 cells and AD mouse models. The authors claimed that diosmetin can effectively cure AD-like pathology by improving skin barrier dysfunction and reducing the severity of dermatitis and other skin inflammatory diseases. These are preclinical findings.
For periodontitis, human periodontal ligament cells (HPDLCs) were induced with LPS. The study found that diosmetin treatment reduced oxidative stress and pro-inflammatory factor secretion by regulating the Nrf2/NF-κB/NLRP3 pathway, thereby mitigating periodontitis. Again, this is in vitro evidence.
Evidence grade: Preclinical only (in vitro, animal models); no human clinical trials completed with diosmetin as primary treatment.
Research provides a comprehensive analysis of different cancer targets and their role in breast, colon, hepatic, gliomas, leukemia, lung, prostate, and skin cancer.
Breast cancer: Diosmetin has been examined for its ability to inhibit proliferation of breast adenocarcinoma cell lines. Research on MDA-MB 468 cells found that diosmetin is selective for cancer cells compared to normal breast cells, with effects mediated via CYP1 activation and cell cycle progression. These are in vitro findings only.
Prostate cancer: Diosmetin has been shown to suppress human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest. These data derive from cell line studies.
Osteosarcoma: Several studies found that diosmetin exerted antitumor effects on liver cancer and breast cancer through inhibiting tumor proliferation, inducing tumor cell apoptosis, and regulating tumor cell cycles. Work in osteosarcoma cells provided a promising strategy that diosmetin may be used in clinical practice for the treatment of osteosarcoma and revealed that STAT3 might be a promising therapeutic target.
Note on data quality: At least one notable diosmetin–cancer paper (on non-small cell lung cancer and paclitaxel) was retracted by the British Journal of Pharmacology in 2024. The overall anticancer evidence for diosmetin remains entirely preclinical; no phase I, II, or III human trials with diosmetin as an anti-cancer agent have been reported in the literature reviewed.
Evidence grade: Animal models and ex vivo human tissue; limited direct human clinical evidence for diosmetin specifically.
Diosmetin is a flavonoid found in many important medicinal plants that have antihypertensive therapeutic potential. Diosmetin has been shown to have antiplatelet, anti-inflammatory, and antioxidant properties, which suggests that it could be a potential candidate for use in antihypertensive therapy.
In a rat model of hypertension, diosmetin significantly decreased the mean arterial pressure (MAP). The effects of diosmetin on the MAP and heart rate were more pronounced in hypertensive rats.
In a rat model of myocardial infarction, the cardioprotective potential of diosmetin on isoproterenol-induced MI in rats was evaluated by performing lead II ECG, cardiac biomarkers including troponin I (cTnI), CPK, CK-MB, LDH, ALT, and AST, as well as histopathological analysis. Diosmetin (1 and 3 mg/kg) attenuated isoproterenol-induced elevation in the T-wave and deep Q-wave on the ECG.
The major human clinical evidence relates to diosmin (the glycoside) as used in preparations such as Daflon® and Detralex® for chronic venous insufficiency, where diosmetin is the circulating active metabolite. A systematic review was carried out to assess the existing evidence for the impacts of diosmin and diosmetin on venous and arterial cardiovascular disorders and related factors. However, clinical trials assessing isolated diosmetin (rather than diosmin or MPFF) specifically for cardiovascular endpoints remain limited.
Evidence grade: Animal models; no completed human clinical trials.
In a murine model of acute hepatic failure (AHF) induced by LPS/D-galactosamine endotoxin, diosmetin decreased mortality among mice, blocked the development of histopathological changes and hepatic damage, and suppressed levels of inflammatory mediators and cytokines. Diosmetin prevented the expression of phosphorylated IKK, IκBα, and NF-κB p65 in the NF-κB signaling pathway, and JNK and p38 in the MAPK signaling pathway. Diosmetin also inhibited hepatocyte apoptosis. Thus, diosmetin exerts protective effects against endotoxin-induced acute hepatic failure in mice.
The mechanism involves multiple complementary pathways: the underlying mechanisms are antioxidation, NF-κB signaling inhibition, inflammatory mediator/cytokine attenuation, and hepatocyte apoptosis suppression.
Evidence grade: Ex vivo human skin tissue; murine models; no completed randomized controlled human trials specifically for diosmetin.
It has been found that diosmetin has significant therapeutic effects on skin and cardiovascular system diseases. In ex vivo human skin explants, diosmetin-3-O-β-D-glucuronide (its main circulating metabolite) induced a significant decrease in hydrogen peroxide production and in the number of CPD-positive cells in UVB-irradiated skin fragments, reaching a maximal effect at a concentration of 2700 pg/mL (−48.6% and −52.0%, respectively). This points to potential photoprotective and antioxidant activity at physiologically relevant plasma concentrations.
Evidence grade: Animal model only.
Research has aimed to explore how diosmetin reduces oxidative stress and inflammation in the ovaries and slows the pathological development of polycystic ovary syndrome by influencing the AKT/PPARγ signalling pathway. This is based on preclinical data; no human trials on PCOS with diosmetin have been identified.
Evidence grade: Preclinical (in vitro and animal models) only.
Diosmetin has anti-inflammatory, anticancer, antimicrobial, phytoestrogen, and neuroprotective properties. Preclinical studies have investigated its capacity to reduce neuronal apoptosis and modulate neuroinflammation via PI3K/AKT/NF-κB signaling. Diosmetin was found to alleviate neuronal damage induced by advanced glycosylation end products by targeting peroxisome proliferator-activated receptor γ (PPARγ). Human evidence is absent.
Evidence grade: Preclinical only.
Both diosmetin 7-O-β-L-arabinofuranosyl apiofuranoside and diosmetin apiofuranoside caused a marked improvement in blood glucose homeostasis in diabetic rats. Diosmetin demonstrates metabolic regulation among its range of pharmacological activities. No human clinical trials evaluating diosmetin specifically for diabetes or glycemic control have been identified in the peer-reviewed literature.
Diosmetin demonstrates a variety of pharmacological activities, including anticancer, antioxidant, anti-inflammatory, antibacterial, metabolic regulation, cardiovascular function improvement, estrogenic effects, and others. The body systems for which preclinical evidence has been generated include:
Diosmetin as a standalone agent does not have an approved therapeutic dosage in any major jurisdiction. Dosages reported in the peer-reviewed scientific literature are as follows:
No standardized dose has been established for diosmetin as an isolated oral supplement in human subjects.
Diosmetin did not show any detectable adverse effects in an acute toxicity study, suggesting that it may be safe for use in the human body. However, this refers to a single preclinical observation; comprehensive human safety data for diosmetin as an isolated supplement are not available.
The most thoroughly documented and clinically relevant safety concern for diosmetin is its inhibition of cytochrome P450 drug-metabolizing enzymes. Although manufacturers declare safe administration for diosmin-containing products, several data indicate inhibition of drug-metabolizing enzymes or drug transporters by diosmin and its aglycone diosmetin, leading to interactions with drugs. Diosmetin is a potent inhibitor of BCRP, OATPs, and several CYPs.
Specifically: Diosmetin potently inhibited breast cancer resistance protein (BCRP), several organic anion transporting polypeptides (OATPs), cytochrome P450 1A2, 2C19, and 3A4 in the lower micromolar range, whereas diosmin did either not inhibit these proteins or was less potent.
After oral administration of diosmin, only its aglycone diosmetin reaches the systemic circulation. Diosmetin forms complexes with serum albumin and is able to inhibit several cytochrome P450 enzymes. It is therefore reasonable to hypothesize that diosmetin may displace some drugs from serum albumin and inhibit their biotransformation, potentially leading to disruption of drug therapy.
It has been demonstrated that diosmetin is a potent inhibitor of the CYP2C9 enzyme and is able to displace the Site I ligand warfarin from human serum albumin. Because diosmetin may interfere with the pharmacokinetics of several drugs through both of these mechanisms, there is a need to consider the potentially hazardous consequences of the consumption of diosmin together with other drugs.
Diosmin and diosmetin are also PXR and AhR activators. Clinical studies are needed to clarify the in vivo interaction potential.
Based on the above in vitro data, diosmetin may, in theory, increase the plasma concentrations of drugs that are substrates of CYP1A2, CYP2C9, CYP2C19, CYP3A4, BCRP, and OATPs. This is particularly relevant for drugs with narrow therapeutic windows, such as warfarin (a CYP2C9 substrate and albumin-bound drug). The CYP-mediated interaction data reviewed are primarily from in vitro microsomal systems; clinical studies are needed to clarify the in vivo interaction potential.
Pharmacologically, diosmetin possesses anticancer, antimicrobial, antioxidant, estrogenic, and anti-inflammatory activities. Its phytoestrogenic character means that, in principle, it could interact with hormone-sensitive tissues or affect the activity of exogenous hormonal therapies, though direct human clinical evidence for estrogenic safety signals with diosmetin specifically has not been established in the reviewed literature.
The overall safety profile of diosmetin as an isolated dietary supplement in humans remains incompletely characterized. The bulk of safety-relevant data comes from (a) observations made in the context of diosmin-containing pharmaceutical products, where diosmetin is the circulating aglycone, and (b) in vitro enzyme inhibition studies. Long-term human safety studies evaluating oral diosmetin in isolation are not available in the peer-reviewed literature reviewed.
Health conditions that Diosmetin may help support.
Body systems that Diosmetin may help support.
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