IngredientsUrsolic acid (UA) is a naturally occurring pentacyclic triterpenoid belonging to the cyclosqualenoid family. Its systematic chemical name is 3β-hydroxy-urs-12-en-28-oic acid, with PubChem CID 64945 and CAS registry number 77–52-1. It has the molecular formula C30H48O3. The compound possesses a pentacyclic ursane-type carbon skeleton, and it is lipophilic in nature and contributes to the waxy coats on apples and other fruits.
The biosynthesis of ursolic acid begins with the conversion of glucose into acetate, which is then converted into acetyl-CoA and mevalonate. Several intermediate metabolites are produced through enzymatic steps; squalene epoxidase produces 2,3-oxidosqualene, which is converted into α-amyrin and β-amyrin, and the enzyme CYP716A40 then produces ursolic acid from α-amyrin. Studies on the structural modifications of UA have shown that the –OH groups at C3 and at C28 are critical factors influencing the cytotoxic activity of UA and its derivatives.
In terms of the Biopharmaceutical Classification System (BCS), UA is a Class IV compound, meaning it exhibits both low solubility and low intestinal permeability. This fundamentally limits the clinical application of UA because of poor bioavailability. UA possesses diverse pharmacological actions but also some undesirable adverse effects; its low solubility, poor bioavailability, and interaction with gut microbiota after oral administration render its pharmacokinetics elusive, leading to uncertainty in pharmacokinetics–pharmacodynamics (PK-PD) profiles.
Ursolic acid is a naturally occurring pentacyclic triterpene found in various edible herbs, vegetables, whole grains, dietary fibres, and fruits such as apples, cranberries, pears, star fruit, mahogany, and blueberries. It is found in the stem bark, leaves, and peel of Chinese herbs and fruits, and has been shown to have a wide range of pharmaceutical properties.
It is found specifically in Malus pumila (apple), Ocimum basilicum (basil), Vaccinium spp. (blueberries), Vaccinium macrocarpon (cranberry), Olea europaea (olive), Origanum vulgare (oregano), Rosmarinus officinalis (rosemary), Salvia species (sage), and Thymus species (thyme). The family Lamiaceae is a particularly well-known source of triterpenes; the leaves of Rosmarinus officinalis are recognized as the commercial source of UA, with contents reaching up to 2.95%.
UA contents vary considerably in different plants, different parts of plants, and different sources, ranging from 0.091 to 1.58% in five different species of the Lamiaceae family (including Rosmarinus officinalis L., Salvia officinalis L., Satureja montana L., Salvia sclarea L., and Salvia glutinosa L.), and reaching 49.7% in apple pomace and 22.7% in rosemary leaves. In oregano, this bioactive triterpenoid is found primarily in the leaves and flowers, with concentrations typically ranging from 0.4–1.2% of the dry weight, depending on variety, growth conditions, and harvest timing.
Additional botanical sources documented in the scientific literature include Arctostaphylos uva-ursi, Eriobotrya japonica (loquat), Eucalyptus citriodora, Lavandula angustifolia (lavender), Melissa officinalis, Prunus species, Psidium guajava (guava), Punica granatum (pomegranate), Sambucus nigra, and Vaccinium myrtillus (bilberry), among many others. UA has also been detected in commercially available dry fruits and edible wild mushrooms.
Ursolic acid is commercially available in several forms as a dietary supplement. These include standardized plant extracts (typically derived from rosemary, holy basil, or loquat leaf), as well as isolated crystalline UA preparations in powder or capsule form. Because of its poor bioavailability together with low intestinal permeability and solubility, UA can also be incorporated as a component in vesicle-like nanocarrier systems, which exploit its small molecular size. With the purpose of improving water solubility and oral bioavailability, ursolic acid nanoparticles (UANs) have been prepared by emulsion solvent evaporation methods, producing nanosuspensions with a mean particle size around 69.7 nm. The oral bioavailability of ursolic acid nanoparticles was found to be increased 2.68 times compared to raw UA in one study.
Initially, UA was considered pharmacologically inactive, which led to its primary use as an emulsifier in medicinal, cosmetic, and food applications, often in the form of salts such as potassium or sodium ursolic acid. Today the compound is also under active investigation in liposomal and polymeric nanoparticle delivery systems for oncology research.
UA is a bioactive compound found in various healing plants, and was historically utilized in folk medicine long before its active therapeutic properties were fully understood. UA is found in leaves of rosemary, thyme, oregano, lavender, and hawthorn, and has been used as an herb extract in folk medicine for centuries.
The isolation of ursolic acid as a distinct chemical entity dates to the 1920s, when chemists first isolated this compound from the bark of apple trees. It was not until the 1990s that researchers began to detail its potential benefits, from anti-inflammatory properties to its ability to modulate nuclear receptors.
UA was originally found in traditional Chinese medicinal herbs, such as Fructus Mume, Gardeniae Fructus, Fructus Ligustri Lucidi, and Hedyotis diffusa Willd. In Chinese traditional medicine, these plant sources were used for a range of ailments including liver disorders, pain, and as tonics. Ursolic acid is found in Nirgundi Patra (Vitex negundo), which has been employed in Ayurvedic practice to help alleviate inflammation. Although Ayurvedic classical texts do not specifically name "ursolic acid" as an isolated constituent, they describe the gentle heating action of aromatic herbs, and seasonal protocols (Ritu-charya) included mild herbal decoctions of Tulsi (Ocimum sanctum) and rosemary during late winter to kindle Agni, reduce Ama buildup, and gently tone the body's tissues—unknowingly leveraging the protective triterpene.
Sage (Salvia officinalis), a Hippocratic staple, contains over 160 polyphenolic compounds including rosmarinic acid, carnosic acid, and ursolic acid. During early ethnobotanical surveys, scientists noted that traditional European herbalists prized rosemary for memory and muscle cramps; later analysis pointed to ursolic acid among other active constituents.
Folk practitioners used crushed leaves of rosemary or holy basil to make poultices for minor cuts, burns, and skin irritations, while teas and decoctions were consumed to support overall wellness and address digestive and respiratory complaints. In traditional Mediterranean cuisines, herbs rich in ursolic acid appear in herb-infused olive oils; in Nordic countries, wild rosemary-like crowberries and cranberries were harvested in late autumn, dried, and brewed as teas to support energy through cold months.
In herbal remedies, ursolic acid was rarely used in isolation; rather, it functioned as a natural component of herbal combinations, its synergistic action with other plant constituents enhancing the efficacy of traditional formulations.
Oleanolic acid (OA), ursolic acid (UA), betulinic acid (BA), and lanosterol are all examples of pentacyclic triterpenes (PT). Ursolic acid belongs to the ursane-type skeleton, which distinguishes it from oleanolic acid (oleanane skeleton) despite the two being structural isomers with closely related biological activities. Pentacyclic triterpenes are ubiquitously distributed natural products in medicinal and aromatic plants. They share a common lipophilic structure that resembles endogenous ligands of nuclear receptors (NRs), which partly explains their broad pharmacodynamic profile.
Ursolic acid can suppress NF-κB activation by inhibiting IκB kinase and p65 phosphorylation. NF-κB regulates the expression of genes associated with proinflammatory cytokines. Thus, the anti-inflammatory effect of ursolic acid may be exerted through the inhibition of NF-κB, thereby reducing downstream inflammatory markers.
UA inhibits activation, proliferation, and cytokine secretion in T cells, B cells, and macrophages. It inhibits mitogen-induced up-regulation of activation markers and co-stimulatory molecules in T and B cells, and it inhibits phosphorylation of ERK and JNK while suppressing the activation of the immunoregulatory transcription factors NF-κB, NF-AT, and AP-1 in lymphocytes. Treatment of cells with UA prior to allogenic transplantation significantly delayed induction of acute graft-versus-host disease in mice and significantly reduced serum levels of pro-inflammatory cytokines IL-6 and IFN-γ.
Ursolic acid increases antioxidant defenses and decreases oxidative stress and other cellular stresses, including mitochondrial stress and ER stress. The anti-inflammatory actions of ursolic acid are mediated, in part, through inhibition of NF-κB signaling pathways.
Evidence shows that ursolic acid: (1) activates uncoupling protein 1 (UCP1) and AMP-activated protein kinase (AMPK) in adipose tissue, enhancing energy expenditure and fatty acid oxidation; (2) enhances hand grip strength; (3) attenuates atrogin-1 and MuRF-1 in skeletal muscle and blocks muscle atrophy; and (4) induces growth hormone (GH), insulin-like growth factor 1 (IGF-1), and insulin release, which bind to the insulin receptor, phosphorylating insulin receptor substrates and protein kinase B, attenuating serum glucose concentrations. Additionally, an increase in Akt expression leads to up-regulation of mTOR in skeletal muscle, stimulating muscle protein synthesis.
In vitro studies have reported that ursolic acid improves insulin signaling by enhancing insulin receptor β subunit phosphorylation and Akt. Ursolic acid also promotes glucose uptake from the bloodstream into peripheral tissues through up-regulation of GLUT4.
UA has exhibited numerous pharmacodynamic effects on nuclear receptors PPAR, LXR, FXR, and PXR, resulting in anti-inflammatory, anti-hyperlipidemic, and hepatoprotective properties, by lowering lipid accumulation in hepatocytes and mitigating non-alcoholic steatohepatitis (NASH) and its subsequent liver fibrosis.
UA plays a role in cancer cell proliferation, metastasis, apoptosis, and angiogenesis, due to its wide regulation of intracellular signaling pathways, including Wnt/β-catenin, the Hippo signaling pathway, and the PI3K/AKT pathway. UA decreases the proliferation of several types of cancer cells by inhibiting the signal transducer and activator of transcription 3 (STAT3) activation pathway and increasing the rate of apoptosis. Furthermore, UA up-regulates the pro-apoptosis factor Bcl-associated X (Bax) and down-regulates the anti-apoptosis factor B-cell lymphoma-2 (Bcl-2). UA-induced apoptosis also involves secretion of cytochrome c through the mitochondrial death pathway.
The molecular mechanism underlying UA activity in lung cancer cells involves UA's binding to the epidermal growth factor receptor (EGFR), reducing the level of phospho-EGFR, and thus inhibiting the downstream JAK2/STAT3 pathway. Furthermore, UA reduces the expression of VEGF, matrix metalloproteinases (MMPs), and programmed death ligand-1 (PD-L1), as well as the formation of STAT3/MMP2 and STAT3/PD-L1 complexes.
There is currently evidence suggesting that ursolic acid may exert a favorable influence on both anti-inflammatory and antioxidant impact, though the anti-inflammatory and antioxidant activities of ursolic acid had not been systematically evaluated until recently. A 2023 systematic review and meta-analysis aimed to address this by examining the impact of UA on markers of inflammatory and antioxidant activity in both animal models and in vitro systems. The search encompassed databases including PubMed, Web of Science, Google Scholar, and ScienceDirect, up until May 2023. All eligible English-language articles were included, standard mean differences were pooled using a random-effects model, and the final review comprised 31 articles.
Evidence strength: The body of evidence for anti-inflammatory activity is predominantly derived from animal models and in vitro cell studies. Major molecular targets of inflammatory diseases include pro-inflammatory cytokines and their receptors, NF-κB, c-Jun-N-terminal kinases (JNK), and mitogen-activated protein kinases (MAPK)—all targets which UA has been shown preclinically to modulate. Well-controlled human trials specifically evaluating anti-inflammatory biomarkers as the primary endpoint remain sparse.
The most rigorous human clinical evidence for ursolic acid relates to metabolic health. In a randomized, double-blind, placebo-controlled clinical trial, 24 patients (aged 30–60 years) with a diagnosis of metabolic syndrome were treated with ursolic acid 150 mg daily. They were randomly assigned to two groups of 12 patients each, to receive orally 150 mg of ursolic acid or a homologous placebo once a day for 12 weeks. The components of metabolic syndrome, insulin sensitivity (Matsuda index), and inflammation profile (interleukin-6 and C-reactive protein) were evaluated before and after the intervention. After ursolic acid administration, the remission of metabolic syndrome occurred in 50% of patients (P = .005), with significant differences in body weight and body mass index.
Earlier work evaluated the effects of UA on body weight and glucose tolerance in metabolic syndrome patients who received 150 mg of UA per day before breakfast for 12 weeks. Reductions in body weight, body mass index, waist circumference, and fasting blood glucose level were observed, suggesting that UA significantly improves insulin sensitivity.
Key metabolic effects of UA include inhibition of pancreatic α-amylase activity and reduction of blood glucose level both in vivo and in vitro.
Evidence strength: The existing human RCT data on metabolic syndrome are promising but involve very small sample sizes (n = 24 in the key trial). Larger, adequately powered trials are needed before firm clinical conclusions can be drawn.
A series of influential preclinical studies demonstrated that in mouse models of diet-induced obesity, ursolic acid supplementation produced measurable effects on body composition. Ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength, and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. These findings showed that ursolic acid increases skeletal muscle, brown fat, and energy expenditure in a mouse model of diet-induced obesity. These effects were associated with increased strength and exercise capacity, and reduced obesity, improved glucose tolerance, and decreased hepatic steatosis. The preclinical data recommended further studies in humans.
However, the translation to human clinical trials has yielded more equivocal results. Ursolic acid is thought to have an anabolic effect on muscle mass in humans. One clinical, double-blind, placebo-controlled trial conducted for 8 weeks compared the effects of UA and a placebo on muscle strength and mass in young men undergoing resistance training (RT) and consuming a high-protein diet. The Control + RT group (n = 12) received 400 mg/d of placebo, and the UA + RT group (n = 10) received 400 mg/d of UA. Both groups consumed approximately 1.6 g/kg of protein and performed the same RT program. This study found no statistically significant additional effect of UA on muscle strength or mass over resistance training combined with adequate protein intake alone.
A separate trial investigated UA supplementation (450 mg/day) in postmenopausal women with metabolic syndrome: Twenty-six women (61 ± 7 years) were randomized into two groups. Both groups followed a combined exercise program for 8 weeks (twice a week; approximately 60 min at moderate intensity) associated with either UA (450 mg/day) or placebo supplementation. Before and post-intervention, waist circumference (primary outcome), resting blood pressure, fasting blood analyses, body composition, and physical function (secondary outcomes) were evaluated. Greater changes in absolute (mean difference: 1.8 kgf, 95% CI 0.3, 3.2) and relative handgrip strength were observed. This study found the primary outcome (waist circumference) was not significantly different between groups, though the handgrip result was notable.
Tea catechins, soy isoflavones, and ursolic acid are considered interesting candidates to combat sarcopenia, but both more systematic basic research and clinical studies in humans are needed.
Evidence strength: Preclinical evidence for UA's anabolic and anti-atrophy effects is mechanistically compelling, but human RCT evidence is inconsistent and limited by small sample sizes and short durations. The anabolic effect in humans has not been reliably replicated under conditions of adequate protein intake.
Ursolic acid has been one of the most extensively studied natural triterpenoids in oncology research. Particular attention has been paid to UA as an anti-cancer agent; clinical tests suggesting the possibility of practical use of UA have already been conducted.
In lung cancer cell lines, multiple studies have demonstrated that UA inhibits the proliferation of non-small cell lung cancer (NSCLC) cells in a dose- and time-dependent manner while promoting apoptosis. In most studies, apoptosis was confirmed through increased levels of cleaved PARP, as well as caspases 3, 7, and 9. Some studies showed an increase in the expression of the proapoptotic protein Bax and a significant decrease in the expression of the antiapoptotic protein Bcl-2, highlighting the apoptotic effects of ursolic acid on lung cancer cells. In vivo studies revealed that treatment of lung cancer xenografted animals with UA resulted in a decrease in tumor volume and weight.
In colon cancer models, the anti-proliferative, anti-migration, and pro-apoptotic effects of UA in colon cancer cells were mediated through simultaneous modulation of multiple signaling pathways, including MMP9/CDH1, Akt/ERK, COX-2/PGE2, p300/NF-κB/CREB2, and cytochrome c/caspase-dependent pathways.
In melanoma, ursolic acid exerts significant (p<0.01) growth-inhibitory effects on SK-MEL-24 metastatic melanoma cells, with an IC50 of 25 μM.
Regarding clinical pharmacokinetics, ursolic acid has been evaluated as a promising anticancer agent in a phase I pharmacokinetic study of ursolic acid nanoliposomes (UANL) in healthy volunteers and patients with advanced solid tumors. Twenty-four healthy volunteers in the single-dose PK study received 37, 74, and 98 mg/m² of UANL. Eight patients in the multiple-dose PK study were administered 74 mg/m² of UANL daily for 14 days. Plasma UA concentrations were determined using ultra-performance liquid chromatography-tandem mass spectrometry. The plasma concentration profiles of all subjects were characterized by a biexponential decline after infusion, and the mean peak plasma concentration (Cmax) increased linearly as a function of dose. A scoping review of nanoparticle-delivered UA for cancer therapy concluded that nanoparticles can increase the anticancer efficacy of UA in terms of pharmacokinetic data, survival rates, and inhibition rates, with an absence of serious toxicity in preclinical and clinical trials. The liposome carrier system has reached the clinical trial phase I.
Evidence strength: Anticancer evidence for UA is extensive in vitro and in animal models. Phase I pharmacokinetic data in humans are available for nanoliposomal formulations. There are currently no published Phase II or III human trials demonstrating efficacy in cancer treatment. Evidence remains at the preclinical to early-phase translational stage.
Ursolic acid has demonstrated significant immunomodulatory and hepatoprotective effects, though underlying mechanisms remain an active area of investigation. Numerous studies have demonstrated UA's hepatoprotective properties, which include reducing liver damage brought on by pollutants, alcohol, and metabolic injury.
UA's pharmacodynamic effects on nuclear receptors PPAR, LXR, FXR, and PXR result in hepatoprotective properties specifically by lowering lipid accumulation in hepatocytes and mitigating non-alcoholic steatohepatitis (NASH) and its subsequent liver fibrosis. Findings from murine studies indicate that UA enhances immune balance in the jejunum, fortifies intestinal barrier function, and promotes overall gut health, contributing to liver-protective outcomes.
Evidence strength: Hepatoprotective evidence is primarily preclinical (animal models, cell studies). No well-powered human RCTs specifically evaluating UA as a hepatoprotective agent have been identified.
Emerging evidence points to UA's neuroprotective properties through its ability to attenuate microglial activation and reduce oxidative stress within the central nervous system. This has implications for conditions such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, where chronic inflammation and oxidative stress are contributory factors.
In preclinical studies, UA has been shown to improve cognitive function, reduce amyloid-β plaque deposition, and inhibit the activation of microglia and astrocytes — key mediators of neuroinflammation — in animal models of Alzheimer's disease. These findings highlight the potential of UA to slow the progression of neurodegenerative diseases.
In a mouse model of cognitive impairment induced by a high-fat diet, ursolic acid treatment (10 mg/kg/day, oral) for 20 weeks significantly improved behavioral performance as measured by the step-through test and the Morris water maze task.
Evidence strength: All neuroprotective evidence is currently preclinical. No controlled human clinical trials evaluating UA for cognitive or neurodegenerative endpoints have been identified in the current literature.
Among the pharmacological properties of UA, one can mention protective effects on the heart and blood vessels, alongside anti-inflammatory properties and anabolic effects on skeletal muscles. In rats with diabetic cardiomyopathy (induced by streptozotocin injection), ursolic acid treatment (35 mg/kg, intragastric) for 8 weeks improved cardiac structure and function by attenuating oxidative stress, inflammation (TNF-α, MCP-1, and TGF-β1), and myocardial interstitial injury.
Given UA's effect on PPAR-γ activation and the subsequent downregulation of pro-inflammatory cytokines, it may hold potential in addressing metabolic syndromes including type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), which carry substantial cardiovascular risk.
Evidence strength: Cardioprotective evidence is predominantly preclinical. Human data in this area remain very limited.
UA has antiviral, antibacterial, and antiparasitic properties and a wide spectrum of pharmacological activities against different infections. Jiménez-Arellanes and colleagues (2013) reported antimicrobial activity of UA against Mycobacterium tuberculosis H37Rv.
UA is known for its antibacterial effects against multi-drug-resistant (MDR) Gram-positive bacteria, which seriously threaten human health. Unfortunately, UA's water-insolubility, low bioavailability, and systemic toxicity limit the possibilities of its application in vivo.
Evidence strength: Antimicrobial evidence is in vitro and preclinical. The poor aqueous solubility of UA complicates systemic delivery in infectious disease settings. No human clinical trials for antimicrobial indications have been identified.
UA may augment the resistance of the skin barrier to irritants, prevent dry skin, and could be suitable for developing anti-aging products. Ursolic acid is widely diffused in plants and has been used in cosmetic preparations, highlighting its importance as a natural ingredient in skincare and beauty products.
Evidence strength: Skin and cosmetic applications have a long history of topical use and are supported by the compound's historical role in the waxy surface coatings of fruits and herbs. Controlled clinical trial data for specific dermatological indications are lacking.
UA supplementation or treatment can provide positive health outcomes via diverse molecular signaling and mechanisms under various diseases in multiple organs, including cancer cells, adipose tissue, the heart, blood vessels, the brain, the liver, and skeletal muscle. The principal body systems with documented preclinical or clinical associations include:
Dosages of ursolic acid used in human clinical studies vary depending on indication. The following represent only those dosages specifically stated in published clinical research:
As a BCS Class IV compound with both low solubility and low permeability, the effective absorbed dose in humans is expected to differ substantially from the nominal administered dose. Poor bioavailability limits clinical application of conventional oral formulations.
UA possesses diverse pharmacological actions but also some undesirable adverse effects and even some toxicological activities. UA has an LD50 value of 9.26 g/kg in acute toxicity tests in mice. Prolonged administration of excessive doses has the potential to cause liver cytotoxicity, which is not classified as genetic toxicity.
A scoping review of nanoparticle-delivered UA found an absence of serious toxicity in preclinical and clinical trials, as measured by body weight, blood clinical chemistry, and organ histopathology parameters. In the human clinical trials reviewed, oral doses of 150–450 mg/day for up to 12 weeks did not generate reports of serious adverse events in the published literature.
Although UA is endowed with numerous in vitro pharmacological activities, it is poorly administered in vivo due to its water insolubility, low bioavailability, and residual systemic toxicity, making urgent the development of water-soluble UA formulations. Due to UA's low solubility and poor bioavailability, and its interaction with gut microbiota after oral administration, the pharmacokinetics of UA remain elusive, leading to obscurity in the PK-PD profile.
Three components of pomegranate juice — namely, ursolic acid, oleanolic acid, and gallic acid — were able to inhibit transmembrane transporters, potentially preventing pharmacological molecules from entering cells and interacting with their molecular targets. This in vitro finding suggests that concentrated UA supplementation could theoretically interfere with the cellular uptake of co-administered drugs through membrane transporter inhibition, though the clinical significance of this at typical supplemental doses has not been established in controlled human studies.
UA's water-insolubility, low bioavailability, and systemic toxicity at high doses limit the possibilities of its application in vivo. Consequently, the beneficial activities of UA observed in vitro lose their potential clinical relevance unless water-soluble, non-cytotoxic UA formulations are developed. These bioavailability challenges mean that the dose required to achieve therapeutically relevant tissue concentrations may differ substantially from the dose studied in preclinical systems.
UA is a natural pentacyclic triterpenoid compound existing in various traditional Chinese medicinal herbs; it possesses diverse pharmacological actions and some undesirable adverse effects, even toxicological activities. Due to UA's low solubility and poor bioavailability, and its interaction with gut microbiota after oral administration, the pharmacokinetics of UA remain elusive, leading to obscurity in the PK-PD profile and relationship for UA. The interactions between UA and gut microbiota are a recognized but incompletely understood dimension of its safety and efficacy profile.
Formal drug interaction studies specifically examining ursolic acid as a supplement against commonly prescribed medications (anticoagulants, antidiabetics, statins) in controlled human settings have not been published in the peer-reviewed literature identified for this article. The potential for UA to affect transporter function, as observed with other pentacyclic triterpenoids, warrants attention in contexts of polypharmacy.
Health conditions that Ursolic acid may help support.
Body systems that Ursolic acid may help support.
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