IngredientsRhamnetin (2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-7-methoxychromen-4-one) is a secondary metabolite belonging to the flavonoid class, present in various plants and fruits. Rhamnetin (molecular formula C16H12O7) is a flavonoid belonging to the flavonol class and commonly exists as an O-glycoside.
The chemical structure features hydroxyl groups at R1, R3 and R4, has hydrogen at R5, and is methoxylated at R2. Rhamnetin is an O-methylated flavonoid, a type of chemical compound. More precisely, rhamnetin is a phenolic flavonoid compound and a methylated derivative of quercetin commonly found in fruits and vegetables.
The compound carries CAS number 90-19-7 and is known by several synonyms including CI-75690, 7-Methoxyquercetin, 7-Methylquercetin, NSC 19802, LY805921, and β-Rhamnocitrin.
The term "rhamnetin" is derived from "Rhamnus," a genus of plants in which the compound was first identified, combined with the suffix "-etin," a common ending in the nomenclature of flavonoids.
The structure of the molecule was discovered by Austrian chemist Josef Herzig (1853–1924). Historical records indicate an early chemical characterization: J. Herzig, writing in the Chemisches Centralblatt (Vol. II, 1891), established rhamnetin to be the methyl ether of quercetin and assigned it the formula C16H12O7, or C15H9O6(OCH3).
Rhamnetin is the aglycone of xanthorhamnin. Xanthorhamnin can be isolated from buckthorn berries (Rhamnus catharticus), and rhamnetin is its aglycone.
Rhamnetin, a methylated derivative of quercetin, is naturally found in a variety of plant sources, such as halophytes (e.g., Halimione portulacoides, Salicornia europaea, Arthrocnemum macrostachyum), vegetables (e.g., Thymus nummularius, Ziziphus mistol), and fruits like clove, apple, and sour cherries. Rhamnetin can be found in cloves, sweet wormwood, and green vegetables such as coriander leaves and seeds; similar amounts are found in apple pomace, peanuts, sour cherries, and radishes.
The genus Rhamnus (Rhamnaceae) is known to be rich with phenolic substances, such as flavonoids, anthraquinones, and naphthalenes. Among the chemicals identified in plants related to the Rhamnus genus are quercetin, rhamnetin, kaempferol, kaempferide, rhamnazin, anthrones, isorhamnetin, rhamnocitrin, and naphthalene derivatives.
The botanical relationship between rhamnetin and xanthorhamnin was documented historically in phytochemical analyses: the unripe and dried berries of Rhamnus species are extracted with boiling water for about 6 hours and the extract evaporated under reduced pressure; the dry powder obtained is a crude commercial xanthorhamnin, which is a mixture of three coloring matters, namely rhamnazin, rhamnetin, and quercetin.
Achyrocline satureioides, Coriandrum sativum, and Rhamnus petiolaris are species that show the presence of 3-O-methylquercetin (3MQ), rhamnetin (Rhm), and rhamnazin (Rhz), respectively, and have anti-inflammatory activities.
Rhamnetin in nature commonly exists as a free aglycone or in glycosidic form. The compound commonly exists as an O-glycoside. Among phenolic chemicals isolated from Rhamnus plant components, rhamnetin-3-O-rhamninoside has been identified as one of the most abundant flavonol forms. In research and commercial settings, isolated rhamnetin is available as a purified powder with purity grades at or above 98% from chemical suppliers. It is used in laboratory studies in dissolved form (typically in dimethyl sulfoxide for in vitro experiments) and has been administered orally in animal models.
Rhamnetin is not itself a traditional medicine per se; its traditional significance is inseparable from the plants of the genus Rhamnus and related species in which it is a constituent phytochemical. The Rhamnus genus is used traditionally to treat diseases such as cancer, wound, jaundice, hepatitis, gonorrhea, as a laxative, for hypertension, malaria, stomach ache, snake bite, and diarrhea. Anthraquinones and flavonoids are the most cited compounds from the genus, of which polyphenols were abundant with tremendous antioxidant, wound-healing, and anti-inflammatory activities.
Plants of the Rhamnus genus have been used in traditional medicine as antioxidants, radical scavengers, anti-inflammatory agents, and for the treatment of liver disorders, constipation, and as laxatives.
Rhamnus davurica Pall. (Rhamnaceae), a shrub or small tree mainly distributed in Northeast China (Dongbei), commonly grows in valleys and on mountain slopes. The medicinal parts—barks, leaf, and seeds—have long been consumed traditionally as a folk remedy for the treatment of dysuresia, pruritus, and constipation in China and other Asian countries. R. davurica has been used as a traditional medicinal herb for many years in China and abroad and has been documented as a rich source of flavonoids with diversified structures, resulting in far-ranging biological activities such as anti-inflammation, anticancer, antibacterial, and antioxidant activities.
Rhamnus prinoides L'Herit has long been widely consumed as folk medicine in Kenya and other African countries. In Ethiopia, leaves of R. prinoides are used in the preparation of traditional beverages. R. prinoides leaves are extensively consumed orally as a component of a local beverage called Tella and Tej.
Rhamnus alaternus is a perennial dioecious shrub growing in the Mediterranean area and is known as a popular medicinal plant widely reported in literature to have excellent antioxidant potential in addition to various biological properties such as antimutagenic, antigenotoxic, antihyperlipidemic, and antimicrobial activities due to its richness in phytochemical compounds belonging to different families like anthraquinones, flavonoids, and anthocyanins.
Beyond medicinal use, Rhamnus berries containing rhamnetin and related flavonols have been historically exploited as natural dyes. The berries of species such as Rhamnus infectoria are known as "French berries" and yield several yellow coloring matters; they contain about 12 percent of glucosidal coloring matters. The glycoside xanthorhamnin was thus an early natural colorant, with rhamnetin being liberated upon hydrolysis. Diluted acids split xanthorhamnin into rhamnetin and isodulcit, and the decomposition is also brought about by ferments existing in the berries themselves, making rhamnetin a prominent constituent of the latter.
The basic structure of flavonoids comprises a chromone group (A and C rings) replaced with a phenyl group (B ring). The variety of flavonoids found in fruits and vegetables (over 5,000 already identified) is due to differences in the basic structures of their functional ligand groups. Flavonoids can be divided into various classes, the important ones being flavones, flavonols, isoflavones, flavanones, and anthocyanidins.
Rhamnetin belongs specifically to the flavonol subclass and is structurally distinguished from its parent molecule quercetin by a 7-O-methyl substitution. The methylation of free hydroxyl groups in flavones results in more metabolically stable derivatives with superior membrane-penetrating properties and thus vastly improves bioavailability, which should improve their ability to act inside cells.
Rhamnetin (Rhm), 3-O-methylquercetin (3MQ), and rhamnazin (Rhz) are methylated derivatives of quercetin commonly found in fruits and vegetables that possess antioxidant and anti-inflammatory properties. The degree and position of methylation critically determine the pharmacological profile: the type of compound and the degree of methylation influence antioxidant capacity, and the number of hydroxyl groups is another parameter that determines antioxidant activity.
In cardiomyoblast studies, rhamnetin protected cells against hydrogen peroxide-induced cell death without cytotoxicity, and also enhanced the expression of catalase and Mn-SOD, thereby inhibiting production of intracellular reactive oxygen species (ROS). Rhamnetin also recovered the H2O2-induced decrease in phosphorylation of Akt/GSK-3β and MAPKs (ERK1/2, p38 MAPK, and JNK), and pretreatment with their inhibitors attenuated the rhamnetin-induced cytoprotective effect.
Rhamnetin suppressed mouse macrophage inflammatory protein (MIP-1, MIP-2), and mouse TNF-α cytokine production in LPS-stimulated macrophages.
A noteworthy anti-neuroinflammatory mechanism involves the alpha-7 nicotinic acetylcholine receptor (nAChR). The alpha7 nicotinic acetylcholine receptor (nAChR) is a potential target in neuroinflammation. Screening a plant extract library identified Solidago nemoralis as containing methyl-quercetin derivatives that are relatively selective ligands for the alpha7 nAChR. Flavonoids are not known for this activity, so researchers screened a small library of pure flavonoids to confirm these findings. Rhamnetin displaced a selective alpha7 nAChR radioligand from rat brain membranes, whereas similar structures (e.g., sakuranetin) did not. Both rhamnetin and sakuranetin reduced mediator release, but differed in potency (rhamnetin > sakuranetin) and the Hill slope of their concentration–response curves.
In astrocytes, the anti-inflammatory mechanism is well characterized: rhamnetin attenuates bradykinin-enhanced MMP-9 upregulation through inhibiting PKCδ/NOX/ROS/ERK1/2-dependent NF-κB activity in rat brain astrocytes.
In enzyme-level studies: rhamnetin exhibited secretory phospholipase A2 (sPLA2) inhibitory potential with no toxicity, and remarkably decreased creatine kinase (CK) levels; the presence of 3-OH on the C-ring of rhamnetin may contribute to both its anti-inflammatory and enzymatic inhibition of sPLA2, and the methylation of ring A may provide the increase in cell viability and low CK levels.
Studies using real-time PCR and a sirtuin inhibitor showed that cardioprotection by rhamnetin occurred through induction of SIRT3 and SIRT4. Rhamnetin protected cardiomyoblasts against H2O2-induced cell death, also enhancing cell protection against redox imbalance. These effects were ascribed to a modulation of mitogen-activated protein kinases (MAPKs), which were upstream influenced by an induction of both SIRT3 and SIRT4 expression, thus supporting rhamnetin's cardioprotection.
Rhamnetin has demonstrated significant anticancer effects across various malignancies, exerting its influence through multiple mechanisms. In prostate cancer, rhamnetin induces apoptosis by modulating the Bax/Bcl-2 ratio, leading to mitochondrial membrane permeabilization, cytochrome c release, and caspase activation. Additionally, it inhibits androgen receptor signaling, a key driver of prostate cancer progression, particularly in androgen-dependent forms of the disease. Rhamnetin also suppresses the hyperactive PI3K/AKT pathway, which contributes to reduced cell survival and proliferation.
Mechanisms include regulation of oxidative stress, inhibition of DNA repair pathways, modulation of signaling pathways such as Notch-1, prevention of epithelial–mesenchymal transition (EMT) and metastasis, induction of apoptosis through mitochondrial pathways, and suppression of angiogenesis.
In non-small cell lung cancer (NSCLC): epithelial–mesenchymal transition induced by radiation was notably attenuated in the presence of rhamnetin in NSCLC cells, demonstrating that rhamnetin can act as a novel radiosensitizer to enhance the efficacy of radiotherapy by inhibiting irradiation-induced Notch-1 expression and its signaling pathways associated with radioresistance.
In hepatocellular carcinoma (HCC): rhamnetin treatment reduced proteins belonging to the Notch-1 signaling pathway and MDR-related pathway, and acts as a promising sensitizer to chemotherapy; it may be a novel approach to overcoming the multi-drug resistance (MDR) process of HCC.
Evidence level: Preclinical (in vitro and animal); no human clinical trials identified.
Rhamnetin is a secondary metabolite belonging to the flavonoid class and has different pharmacological properties including antioxidant, anticancer, anti-inflammatory, antiviral, and antibacterial activity. Antioxidant evidence is derived principally from cell-based and animal models. Studies investigated the protective effects of rhamnetin against H2O2-induced apoptosis in H9c2 cardiomyoblasts; rhamnetin protected cells against H2O2-induced cell death without any cytotoxicity, as determined by XTT assay, LDH assay, TUNEL assay, Hoechst 33342 assay, and western blot analysis of apoptosis-related proteins. These studies are entirely preclinical, and direct extrapolation to human antioxidant benefit cannot be made.
Evidence level: Preclinical (in vitro and animal models); no human clinical trials identified.
Multiple mechanistically distinct lines of preclinical evidence support anti-inflammatory activity. In a macrophage model, rhamnetin suppressed mouse macrophage inflammatory protein (MIP-1, MIP-2) and mouse TNF-α cytokine production in LPS-stimulated macrophages.
In the sPLA2 inhibition study (in vivo, mouse), cytotoxic studies were performed using the J774 cell lineage, and in vivo tests were performed with Swiss female mice to evaluate decreasing paw edema potential and compounds' creatine kinase levels. Results showed that rhamnetin can be a candidate as a natural compound for the development of new anti-inflammatory drugs.
A gastroprotective study tested rhamnetin in an indomethacin-induced ulceration rat model: animals were divided into five groups including low-dose (30 mg/kg) and high-dose (60 mg/kg) rhamnetin groups, and the findings characterized both anti-inflammatory and gastroprotective effects.
The anti-neuroinflammatory evidence is notable in the context of microglial biology: to evaluate the contribution of the putative nAChR activity to the known anti-inflammatory properties of these flavonoids, researchers compared their effects on LPS-induced release of inflammatory mediators from BV2 microglia; both rhamnetin and sakuranetin reduced mediator release, but differed in potency.
All anti-inflammatory findings to date are from cell culture or animal models. No randomized clinical trials in humans have been reported for rhamnetin's anti-inflammatory activity as an isolated compound.
Evidence level: Preclinical (in vitro); no human clinical trials identified.
Rhamnetin, a commonly occurring plant O-methylated flavonoid, shows cardioprotection via induction of SIRT3 and SIRT4 (Park et al., 2014). This finding originates from H9c2 cardiomyoblast cell experiments. Rhamnetin protected cardiomyoblasts against H2O2-induced cell death, enhancing cell protection against redox imbalance; these effects were ascribed to a modulation of MAPKs, upstream influenced by an induction of both SIRT3 and SIRT4 expression.
Rhamnetin is a phenolic flavonoid compound possessing various pharmacological activities, such as cardioprotective, anti-inflammatory, anti-oxidative, and anti-apoptotic effects. The cardioprotective evidence is currently confined to in vitro cardiomyoblast models, with no reported in vivo cardiac studies using isolated rhamnetin and no human trials.
Evidence level: Preclinical (in vitro cell lines; limited animal tumor models); no human clinical trials identified.
Rhamnetin, a naturally occurring compound found in various plants, has emerged as a promising candidate in cancer therapy due to its diverse range of biological activities. It has demonstrated the ability to induce programmed cell death in cancer cells, inhibit the formation of new blood vessels that support tumor growth, and prevent the transition of cancer cells to more invasive forms. Rhamnetin also regulates oxidative stress and mitochondrial function, contributing to its anticancer effects.
Prostate cancer: Studies using prostate cancer cell lines such as PC-3 and LNCaP showed increased caspase activity and decreased androgen receptor (AR) expression following rhamnetin treatment, correlating with reduced cell viability.
Gastric cancer: In gastric cancer, rhamnetin works by inducing cell cycle arrest at the G1 phase, primarily through the downregulation of cyclin D1 and CDK4/6, while upregulating inhibitors.
Non-small cell lung cancer: Researchers investigated the use of Notch-1-regulating flavonoid compounds as novel therapeutic drugs to regulate radiosensitivity in NSCLC cells (NCI-H1299 and NCI-H460, with different levels of radioresistance); rhamnetin and cirsiliol were selected as candidate Notch-1-regulating radiosensitizers based on activity assay screening. Investigation of the relationship between apoptosis and activation of the NF-κB pathway in NSCLC cells showed that IκBα phosphorylation, nuclear translocation of p65, and NF-κB transcriptional activation increased by irradiation were suppressed by treatment with rhamnetin and cirsiliol.
Hepatocellular carcinoma: This study investigated the potential application of rhamnetin as a specific inhibitor of the Notch-1 pathway in anti-tumor drug sensitization of HCC treatment. Rhamnetin, a flavonoid compound also containing polyphenol structure extracted from Hippophae rhamnoides Linn, induced radiosensitization by inhibiting Notch-1 pathway via enhancing miR-34a level, the dominant negative regulator targeting Notch-1.
Breast cancer: Published work referenced in the literature indicates that rhamnetin induces apoptosis in human breast cancer cells via the miR-34a/Notch-1 signaling pathway (Lan et al., Oncology Letters, 2019).
Despite a wealth of preclinical evidence supporting rhamnetin's potential, there is a significant gap in robust clinical trials to validate its safety, efficacy, and optimal dosage in humans. All anticancer evidence currently resides at the in vitro and limited animal model level, and no human oncology trials have been reported.
Evidence level: Preclinical (in vitro and animal models); no human clinical trials identified.
A key study examined rhamnetin in a rat traumatic brain injury (TBI) model: the study aimed to detect possible effects of rhamnetin on cognitive deficit, hippocampal inflammatory factors, and oxidative stress in rats with TBI; a traumatic brain injury model was established in rats, which received vehicle saline or rhamnetin for 21 days; cognitive functions were evaluated by assessing acquisition of spatial learning and memory retention in the Morris Water Maze test from day 15 to 19 post-TBI. Levels of interleukin (IL)-1β, IL-6, IL-8, TNF-α, IL-10, and NF-κB in hippocampal homogenate were measured using ELISA, and oxidative stress was analyzed by investigating MDA, H2O2, SOD, and GSH-Px activities. Findings showed that rhamnetin both improved the cognitive deficit induced by TBI and inhibited overproduction of hippocampal inflammatory mediators, including NF-κB and oxidative stress markers.
In a cell-based neuroinflammation model: rhamnetin has been demonstrated to be an effective therapeutic agent in many diseases related to inflammation, including cancer, ischemia, and traumatic brain injury; a growing body of evidence has indicated that rhamnetin or its derivatives possess anti-inflammatory effects via protecting against oxidative stress, targeting MMPs, and regulating the activation of protein kinases and transcription factors.
Evidence level: Preclinical (in vitro); no human clinical trials identified.
As a bioflavonoid, rhamnetin exhibits a broad range of therapeutic properties, including neuroprotective, anti-inflammatory, antioxidant, ischemia-preventive, antibacterial, and anticancer effects. Pharmacological activity evaluation of extracts and isolated compounds from Rhamnus species revealed anti-inflammatory, antioxidant, antimalarial, antibacterial, antimutagenic, antigenotoxic, hepatoprotective, anticancer, and antiproliferative activity. These findings largely derive from in vitro minimum inhibitory concentration studies and enzyme inhibition assays. No human clinical trials for rhamnetin's antimicrobial or antiviral properties have been identified.
Evidence level: Preclinical (animal model); no human clinical trials identified.
Despite rhamnetin's numerous biological potentials—such as anti-inflammatory, antioxidant, and antimicrobial effects—there is a lack of literature elucidating its gastroprotective action and anticipating molecular mechanism. Natural products can be a good alternative to overcome the side effects and relapses associated with anti-ulcer drugs. A study aimed to elucidate rhamnetin's acute toxicity and gastroprotective effects using the indomethacin ulceration model. This preclinical (animal) research represents early-stage evidence only.
There are no established human dosages for rhamnetin as an isolated compound. The following dosages have been reported exclusively in preclinical (animal) studies:
No standardized formulations (tablets, capsules, tinctures) of purified rhamnetin are currently approved or commercially available as regulated pharmaceutical preparations. Research-grade isolates are available for laboratory use.
Rhamnetin's low bioavailability, stemming from poor solubility and rapid metabolism, limits its therapeutic potential. However, the methylation of its hydroxyl group confers a relative advantage over non-methylated analogues: the methylation of free hydroxyl groups in flavones results in more metabolically stable derivatives with superior membrane-penetrating properties and thus vastly improves bioavailability, which should improve their ability to act inside cells. Enhancing delivery—through nanoformulation or structural modification—is an active area of pharmaceutical research for rhamnetin and related flavonols, though formal human pharmacokinetic data have not been published for the isolated compound.
Rhamnetin is present in various plants and fruits and has different pharmacological properties; however, conclusive results on the toxicology of rhamnetin have not been reported yet, and further research is needed to gather detailed information about the effects of rhamnetin.
Rhamnetin exhibits a favorable safety profile at therapeutic doses, with potential adverse effects primarily associated with supratherapeutic levels. Its hepatoprotective, nephroprotective, and neuroprotective properties, along with its lack of genotoxicity and immunotoxicity, make it a promising candidate for therapeutic applications. However, further research into optimal dosing strategies, long-term safety, and the mitigation of dose-dependent toxicity is essential for advancing rhamnetin toward clinical use.
In the rat acute toxicity study: toxicity evaluations indicated the safety of rhamnetin at doses of up to 400 mg/kg in rats, without any noticeable physiological alterations.
Despite a wealth of preclinical evidence supporting rhamnetin's potential, there is a significant gap in robust clinical trials to validate its safety, efficacy, and optimal dosage in humans; translating the promising preclinical findings into clinical practice remains a major challenge.
Rhamnetin is a methylated quercetin derivative. Because quercetin and related flavonols can interact with cytochrome P450 enzymes involved in drug metabolism, analogous interactions with rhamnetin are plausible, but specific drug–rhamnetin interaction data have not been published for the isolated compound in humans. The structural characteristics of methylated flavonoids may contribute to both antioxidant activity and potential toxicity at higher concentrations.
In the sPLA2 inhibition study, cytotoxic evaluation was performed to screen for cellular safety: rhamnetin exhibited sPLA2 inhibitory potential and no toxicity in the cell viability assays used.
A review of rhamnetin's salient properties and pharmacological potential was carried out using the ScienceDirect database; a total of 573 research articles were extracted, and only those reporting evidence of possible pharmacological applications of rhamnetin were included; publications range from 1977 to 2021.
The overall body of evidence for rhamnetin remains at an early, predominantly in vitro and animal-model stage. Despite its numerous biological potentials, such as anti-inflammatory, antioxidant, and antimicrobial effects, there is a lack of literature elucidating certain pharmacological actions and their anticipating molecular mechanisms in depth. No randomized controlled clinical trials (RCTs) in humans examining rhamnetin as an isolated intervention for any health condition have been identified in the peer-reviewed literature as of the most recent published reviews. The compound's scientific profile qualifies it as a research-stage phytochemical rather than a clinically validated therapeutic agent.
Health conditions that Rhammetin may help support.
Body systems that Rhammetin may help support.
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