Isorhamnetin

Pharmacology & Research

Isorhamnetin (3′-O-methylquercetin) is a dietary flavonol — quercetin carrying a single methyl group on the 3′ position of its B-ring. That one methyl is why its literature reads two ways at once. In plants isorhamnetin is a widespread flavonol in its own right: the signature flavonol of sea-buckthorn fruit, one of the three principal flavonols of Ginkgo leaf (where it contributes to the radical-scavenging antioxidant fraction of the standardised extract ^{6Reference 6Maitra I et al. · 1995In vitroPeroxyl radical scavenging activity of Ginkgo biloba extract EGb 761 — in vitroView study →}), and a recurring antioxidant constituent across this database — in goldenrod, wormwood, stinging nettle, calendula, elder and African dream herb — almost always stored as glycosides ^{1Reference 1Gong G et al. · 2020ReviewIsorhamnetin: A review of pharmacological effects — reviewView study →}. In people it is also a major circulating metabolite of quercetin and rutin: catechol-O-methyltransferase methylates quercetin’s 3′-hydroxyl, so isorhamnetin appears in blood after any quercetin-rich intake and is part of what quercetin’s activity actually reflects ^{1,7Reference 1Gong G et al. · 2020ReviewIsorhamnetin: A review of pharmacological effects — reviewView study →Reference 7Jiang H et al. · 2019In vitroQuercetin and its metabolite isorhamnetin promote glucose uptake through different signalling pathways in myotubes — in vitroView study →}. Methylation blocks one of quercetin’s conjugation sites, giving isorhamnetin somewhat better membrane permeability and metabolic stability — but oral bioavailability is still limited, and, as with every flavonol here, the entire applied literature is preclinical: cardiovascular, anti-inflammatory, metabolic, hepatoprotective and anticancer signals from cell and rodent models, with no trial of the isolated molecule in humans ^{1Reference 1Gong G et al. · 2020ReviewIsorhamnetin: A review of pharmacological effects — reviewView study →}.

1. Cardiovascular / vascular

The broadest and most in-vivo signal. Isolated isorhamnetin given to mice for eight weeks after aortic banding blunted pressure-overload cardiac hypertrophy and fibrosis, an effect traced to blocking PI3K–AKT signalling ^{9Reference 9Gao L et al. · 2017AnimalIsorhamnetin protects against cardiac hypertrophy through blocking PI3K–AKT pathway — mouse aortic-banding modelView study →}. In isolated rat hearts it reduced ischaemia-reperfusion infarct size and marker-enzyme release (LDH, CK) dose-dependently, limiting cardiomyocyte apoptosis and oxidative stress (↑Bcl-2, ↓Bax/caspase-3, ↓MDA) ^{10Reference 10Xu Y et al. · 2020AnimalCardioprotective effect of isorhamnetin against myocardial ischemia reperfusion (I/R) injury in isolated rat heart through attenuation of apoptosis — rat modelView study →}. At the vessel wall it protected TNF-α-injured endothelial cells (HUVECs), cutting apoptosis and the adhesion molecules ICAM-1, VCAM-1 and E-selectin via NF-κB suppression while restoring eNOS ^{8Reference 8Chen TL et al. · 2015In vitroProtective effects of isorhamnetin on apoptosis and inflammation in TNF-α-induced HUVECs injury — in vitroView study →}. The pharmacological review catalogues further anti-atherosclerotic and anti-thrombotic actions ^{1Reference 1Gong G et al. · 2020ReviewIsorhamnetin: A review of pharmacological effects — reviewView study →}.

Gap: every result is cell or rodent; there is no human cardiovascular trial, and the doses were not bioavailability-matched to what oral intake achieves.

2. Anti-inflammatory

A consistent mechanistic through-line: isolated isorhamnetin dampens NF-κB-driven inflammation. In LPS-challenged mice it lowered TNF-α, IL-1β and IL-6 and reduced tissue injury by downregulating NF-κB signalling ^{12Reference 12Li Y et al. · 2016In vitroIsorhamnetin ameliorates LPS-induced inflammatory response through downregulation of NF-κB signaling — in vitro and mouse modelView study →}, and in an LPS acute-lung-injury model it attenuated lung oedema, MPO activity and cytokine release (also implicating mTOR) ^{14Reference 14Yang B et al. · 2022AnimalIsorhamnetin alleviates lipopolysaccharide-induced acute lung injury by inhibiting mTOR signaling pathway — mouse modelView study →}. The same NF-κB suppression underlies its endothelial protection ^{8Reference 8Chen TL et al. · 2015In vitroProtective effects of isorhamnetin on apoptosis and inflammation in TNF-α-induced HUVECs injury — in vitroView study →}.

Gap: rodent and cell models only; the anti-inflammatory doses have no human counterpart, and NF-κB inhibition is a shared flavonol mechanism rather than something specific to isorhamnetin.

3. Metabolic / anti-diabetic

Isolated isorhamnetin promotes glucose disposal and opposes adiposity in mechanistic models. In cultured myotubes it increased glucose uptake by translocating GLUT4 — notably through the JAK2/STAT pathway, a different route from quercetin’s CaMKKβ/AMPK, and active at low-nanomolar concentrations ^{7Reference 7Jiang H et al. · 2019In vitroQuercetin and its metabolite isorhamnetin promote glucose uptake through different signalling pathways in myotubes — in vitroView study →}. Dedicated reviews summarise anti-diabetic actions (aldose-reductase inhibition, improved insulin signalling, protection against diabetic complications) ^{2Reference 2Kalai FZ et al. · 2022In vitroEffects of Isorhamnetin on Diabetes and Its Associated Complications: A Review of In Vitro and In Vivo Studies and a Post Hoc Transcriptome Analysis — reviewView study →} and anti-obesity effects (suppressed adipogenesis, PPARγ modulation) ^{3Reference 3González-Arceo M et al. · 2022ReviewAnti-Obesity Effects of Isorhamnetin and Isorhamnetin Conjugates — reviewView study →}.

Gap: the evidence is cell-based or review-level; there are no clinical glucose or weight outcomes for the isolated molecule.

4. Hepatoprotective

Isolated isorhamnetin protects the liver across injury models. In a diet-induced NASH mouse it reduced steatosis and fibrosis at 50 mg/kg — cutting hepatic triglyceride and collagen by downregulating lipogenic (SREBP1c/FAS/ACC1) and fibrogenic (TGF-β/collagen-I) programmes ^{11Reference 11Ganbold M et al. · 2019AnimalIsorhamnetin Alleviates Steatosis and Fibrosis in Mice with Nonalcoholic Steatohepatitis — mouse modelView study →}. In a separate mouse model of chemical liver injury it lowered transaminases and inflammatory cytokines and regulated apoptosis/autophagy via the P38/PPAR-α pathway ^{5Reference 5Lu X et al. · 2018AnimalIsorhamnetin: A hepatoprotective flavonoid inhibits apoptosis and autophagy via P38/PPAR-α pathway in mice — mouse modelView study →}.

Gap: in-vivo but single-laboratory rodent work with no human data; the NASH finding awaits independent replication.

5. Anticancer

The broadest but thinnest signal. Isolated isorhamnetin induces apoptosis and cell-cycle arrest across cultured tumour lines: in human bladder-cancer cells it triggered ROS-dependent G2/M arrest and both intrinsic and extrinsic apoptosis through AMPK activation ^{13Reference 13Park C et al. · 2019In vitroIsorhamnetin Induces Cell Cycle Arrest and Apoptosis Via Reactive Oxygen Species-Mediated AMP-Activated Protein Kinase Signaling Pathway Activation in Human Bladder Cancer Cells — in vitroView study →}, and a 2024 review catalogues similar in-vitro activity (AMPK/mTOR, PI3K-Akt and EMT effects) in breast, gastric, colon and lung lines ^{4Reference 4Lei J et al. · 2024In vitroIsorhamnetin: what is the in vitro evidence for its antitumor potential and beyond? — reviewView study →}.

Gap: almost entirely in-vitro at concentrations the poor oral bioavailability makes hard to reach systemically; in-vivo tumour data are sparse and there are no human oncology data ^{4Reference 4Lei J et al. · 2024In vitroIsorhamnetin: what is the in vitro evidence for its antitumor potential and beyond? — reviewView study →}.

Mechanisms

Target / pathway	Effect	Relevant to
PI3K–AKT	Inhibits → ↓cardiac hypertrophy / fibrosis	Cardiovascular
NF-κB / MAPK, ICAM-1/VCAM-1	Suppresses → ↓inflammation, endothelial protection	Anti-inflammatory, cardiovascular
eNOS	Upregulates → nitric-oxide / endothelial support	Cardiovascular
Bcl-2/Bax, caspase-3/9	Modulates → ↓cardiomyocyte apoptosis (protective)	Cardiovascular
GLUT4 via JAK2/STAT	Activates → ↑glucose uptake	Metabolic
SREBP1c/FAS/ACC1, PPAR-α	Downregulates lipogenesis / regulates lipid metabolism	Hepatoprotective, metabolic
ROS → AMPK → mTOR/p70S6K	Activates (pro-apoptotic in tumour cells)	Anticancer
Radical scavenging (flavonol antioxidant)	Peroxyl/hydroxyl scavenging, ↓lipid peroxidation	General antioxidant

Pharmacokinetics

Isorhamnetin’s defining pharmacokinetic fact is its relationship to quercetin. It is not only a plant flavonol but a major in-vivo metabolite of quercetin and rutin: catechol-O-methyltransferase (COMT) methylates quercetin’s 3′-hydroxyl, so isorhamnetin circulates after any quercetin-rich intake and is part of what quercetin’s activity actually reflects ^{1,7Reference 1Gong G et al. · 2020ReviewIsorhamnetin: A review of pharmacological effects — reviewView study →Reference 7Jiang H et al. · 2019In vitroQuercetin and its metabolite isorhamnetin promote glucose uptake through different signalling pathways in myotubes — in vitroView study →}. Methylating that 3′-OH removes one of the sites available for glucuronidation and sulfation and makes the molecule more lipophilic, which gives isorhamnetin better membrane permeability and metabolic stability than quercetin — the basis for reports that it is more bioavailable than the parent flavonol ^{1Reference 1Gong G et al. · 2020ReviewIsorhamnetin: A review of pharmacological effects — reviewView study →}. “More than quercetin,” though, is a low bar: oral bioavailability remains limited, isorhamnetin is itself extensively conjugated to glucuronides and sulfates, and plasma levels stay low relative to the micromolar concentrations used in most cell studies ^{1Reference 1Gong G et al. · 2020ReviewIsorhamnetin: A review of pharmacological effects — reviewView study →}. As with quercetin, in plants it is stored largely as glycosides (isorhamnetin-3-O-glucoside, isorhamnetin-3-O-rutinoside / narcissin) that must be hydrolysed before absorption. The practical upshot mirrors the other flavonols: potent in-vitro concentrations are not trivially reached by mouth, which tempers every downstream claim.

Clinical trials

There are essentially no registered trials of isolated isorhamnetin. Its human relevance is indirect — it is one of the circulating metabolites measured in quercetin, sea-buckthorn and Ginkgo trials, which are plant- or parent-molecule exposures and cannot be read as isorhamnetin results. Everything on this page is preclinical.

Last checked: July 2026.

Toxicity & Safety

Isorhamnetin carries a low toxicity flag. It is a common dietary flavonol — eaten in onions, pears, sea-buckthorn and leafy herbs — and, unusually, it is also generated inside the body from quercetin, so people are chronically and safely exposed to it at dietary levels ^{1Reference 1Gong G et al. · 2020ReviewIsorhamnetin: A review of pharmacological effects — reviewView study →}. Reviews describe it as well tolerated in animal studies without signature organ toxicity at the doses used, though no formal human safety database exists because the isolated molecule has not been trialled in people ^{1Reference 1Gong G et al. · 2020ReviewIsorhamnetin: A review of pharmacological effects — reviewView study →}. Like other flavonols it can inhibit drug-metabolising cytochrome-P450 enzymes and transporters in laboratory systems, so interactions with medications are plausible but not clinically quantified; reasonable caution applies to anyone combining high-dose flavonol supplements with narrow-margin CYP / P-glycoprotein-substrate drugs. Isorhamnetin also shares quercetin’s caveat that most of its striking in-vitro activity — including the pro-apoptotic anticancer effects — occurs at concentrations well above achievable plasma levels, a potency that does not automatically translate into whole-body effect or harm. No isolated-molecule reproductive or developmental toxicity finding was identified in this pass.

Dosage

There is no established human dose for isolated isorhamnetin. Preclinical work spans cell-culture concentrations from low-nanomolar (glucose uptake in myotubes) to tens of micromolar (anticancer apoptosis), and rodent doses in the tens of mg/kg range — for example 50 mg/kg in the NASH model and 100 mg/kg in the cardiac-hypertrophy study ^{7,9,11Reference 7Jiang H et al. · 2019In vitroQuercetin and its metabolite isorhamnetin promote glucose uptake through different signalling pathways in myotubes — in vitroView study →Reference 9Gao L et al. · 2017AnimalIsorhamnetin protects against cardiac hypertrophy through blocking PI3K–AKT pathway — mouse aortic-banding modelView study →Reference 11Ganbold M et al. · 2019AnimalIsorhamnetin Alleviates Steatosis and Fibrosis in Mice with Nonalcoholic Steatohepatitis — mouse modelView study →}. Because oral bioavailability is limited and the molecule is heavily conjugated, extrapolating any of these to a human dose is speculative. These are doses studied in research and are not a personal recommendation.

References