Ursolic acid as a multifunctional anticancer agent with insights into molecular mechanisms therapeutic potential and formulation strategies

Abstract

The purpose of this review article is to comprehensively summarize the anticancer potential of Ursolic Acid (UA) by elucidating its underlying molecular mechanisms, therapeutic efficacy, and formulation advancements. It aims to highlight UA’s multifunctional role in modulating key cancer-related pathways and discuss recent progress in nano-formulation strategies designed to overcome its poor solubility and bioavailability, thereby facilitating its clinical translation. This review employs a comprehensive analysis of existing preclinical and limited clinical studies on UA, focusing on its molecular mechanisms and anticancer activities. It systematically examines literature related to key signalling pathways, therapeutic effects, and formulation advancements. Additionally, it evaluates nano-formulation approaches and combination therapies aimed at improving UA’s bioavailability and clinical applicability. The review reveals that UA demonstrates strong anticancer potential by inducing apoptosis, autophagy, and cell cycle arrest through modulation of key pathways like PI3K/Akt/mTOR, STAT3, and NF-κB. It suppresses metastasis, angiogenesis, and epithelial-mesenchymal transition, enhances antioxidant defence, and triggers ROS-mediated apoptosis. UA’s epigenetic modulation contributes to its anti-proliferative effects, while nano formulations improve its solubility, bioavailability, and targeted delivery, with early clinical studies showing good tolerance and preliminary signs of therapeutic benefit.UA emerges as a promising natural anticancer agent capable of targeting multiple molecular pathways involved in tumor growth and progression. Despite its broad preclinical efficacy, its poor solubility and low bioavailability limit clinical application. Advances in nano-formulation strategies have shown potential to overcome these challenges. However, extensive clinical investigations and standardized formulations are essential for successful therapeutic translation.

Graphical Abstract

Introduction

Natural bio-actives such as phytochemicals from medicinal plants, fruits, and vegetables play a vital role in cancer prevention and therapy. Roughly 80% of United States Food and Drug Administration (FDA)-approved antineoplastic drugs in the past decades are natural products or mimic natural compounds [1]. Moreover, with the advancement in the manufacturing industry, it is expected that novel compounds from natural origin would be discovered and developed as efficacious anti-neoplastic drugs with high tolerability. Plentiful natural bio-actives have shown their anticancer properties via targeting multiple molecular targets and signalling pathways involved in the pathophysiology of cancer, including phytochemicals such as Ursolic acid (UA) [2].

UA is a naturally occurring secondary metabolite, belonging to the ursane-type pentacyclic triterpenoid, found in medicinal herbs and a variety of fruits and vegetables. They are widely distributed geographically and offer several benefits for human health owing to their high efficacy and tolerability [3]. UA has garnered considerable attention in recent years, mainly against cancer, for its ability to display a plethora of pharmacological activities via acting on multiple molecular entities simultaneously, and the potential to influence several hallmarks of cancer [4]. Numerous preclinical studies have demonstrated that UA significantly inhibits tumor growth by inducing cell cycle arrest and apoptosis [5]. UA also impairs the process critical for tumor nourishment and dissemination, including angiogenesis and metastasis [6–8]. By targeting multiple key players involved in inflammatory and survival pathways, UA sensitizes tumor cells to apoptotic signals. UA also sensitizes cancer cells to cytotoxic drugs when administered as a combination therapy [9]. Mechanistic studies have demonstrated its potential against several human cancer subtypes, including breast, gastric, lung, and colon cancer, via modulating key players involved in the signalling pathways of this multifaceted disease, including oncogenes, transcription factors, cell cycle regulators, apoptotic markers, cytokines, and receptor tyrosine kinases, etc [3]. Importantly, UA displays a favourable safety profile and is generally well tolerated in preclinical models. These attributes underscore the significance of UA as a potential candidate for antineoplastic therapy [10].

However, UA belongs to the biopharmaceutics classification system [BCS) class IV category owing to its low solubility and poor permeability. Therefore, the physicochemical property of UA makes it difficult for UA to solubilize in gastrointestinal fluid and cross the intestinal membrane to enter the bloodstream [2]. This limited oral bioavailability presents challenges for developing it as an oral drug. To overcome these limitations, researchers are exploring various drug delivery strategies, including nano emulsions, solid lipid nanoparticles, liposomes and other delivery systems. This review focuses on UA’s chemistry, sources, molecular mechanisms of anticancer activity, and the latest research toward its development as a complementary cancer therapy via improved drug delivery system and addressal of the concerned challenges.

Sources and chemistry of ursolic acid

UA is widely distributed in various plants, herbs, berries, and non-berries. Many medicinal plants such as rosemary (Salvia rosmarinus), sage (Salvia officinalis), thyme (Thymus vulgaris), oregano (Origanummajorana), basil (Ocimumbasilicum), lavender (Lavandula spp.), and lemon balm (Melissa officinalis) all contain UA as a secondary metabolite. Somehigher plants, shrubs, and woody trees such as privet (Ligustrum lucidum) and oleander (Nerium oleander) accumulate UA mainly in theleafy part of the plant. Many berries, like American cranberry (Vaccinium macrocarpon), highbush blueberry (Vacciniumcorymbosum), and hawthorn fruit (Crataegus monogyna) are a rich source of UA. Additionally, some non-berries, including apple (Malusdomestica), pear (Pyruscommunis), loquat (Eriobotrya japonica, Rosaceae), and Japanese quince (Chaenomeles japonica), have been reported to store UA in the cuticular wax of the peels [11].

UA, scientifically called 3β-hydroxy-urs-12-en-28-oic acid, has a molecular formula of C₃₀H₄₈O₃ and a molecular weight of 456.71 g/mol, characterized by a complex structural composition. The penta-cyclic structure of UA consists of five intersecting carbon rings, which are responsible for its pharmacological activity and stability [3]. The structure has a hydroxyl group at the C-3 position, an alkene group at C12–C13 position, and a carboxylic acid group at the C-28 position. UA is thermally stable, has limited intestinal permeability, and has a very low aqueous solubility, contributing to its low oral bioavailability [4]. Preclinical and human studies indicate that the absorption of UA is compromised due to its low aqueous solubility. Rodent models and human subjects have demonstrated that the plasma concentration of UA reaches a significant level for only a short period due to low absorption capacity and rapid elimination from the body [12, 13]. However, higher doses in humans resulted in higher plasma concentrations, suggesting that high doses of UA might be required to reach therapeutic concentrations. It is well-distributed across body tissues, preferentially accumulating in the lungs and liver, where it is found in higher concentrations in its unaltered form. This suggests that the biological activities of UA come mostly from its unmetabolized form. Toxicity studies in animal studies demonstrated that it is well-tolerated even at higher doses, however, more human studies are required to confirm its safety profile [10].

Preclinical studies and mechanisms of anticancer activity

Numerous preclinical studies (in vitro cell culture and in vivo animal models) have examined UA’s anticancer effects, revealing that UA can modulate multiple hallmarks of cancer. Below sections summarize the various mechanistic.

Antioxidants and ROS-mediated effects

Oxidative stress is known to cause cancer, and its mitigation can aid in cancer prevention and therapy. UA can elevate the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) contributing to the reduction of oxidative stress. UA treatment has demonstrated an increase in the ROS level, inducing apoptosis in human ovarian and oesophageal cancer cells [14, 15]. Additionally, UA can influence redox-sensitive signaling pathways: it activates phase II detoxifying enzymes like NAD(P)H: quinone oxidoreductase 1 (NQO1) and modulates inflammatory redox regulators. For instance, UA inhibited the growth of human breast cancer MDA-MB-231 cells by downregulation of the inflammatory and antioxidant marker nuclear factor E2-related factor 2 (Nrf2) via the Keap1/EGFR/Nrf2 pathway [16].

Apoptosis induction and cell cycle arrest

UA demonstrates its anti-proliferative and pro-apoptotic effects in a variety of human cancer subtypes such as lung cancer [5], ovarian cancer [15, 17], melanoma [18], oral cancer [19], colorectal cancer [20, 21], gastrointestinal cancer [22], prostate and urogenital cancers [23] and breast cancer [24]. targeting multiple signalling pathways, cell cycle regulators such as cyclins D & E and cyclin dependent CDKs 2/4 and activation of both the intrinsic and extrinsic apoptotic pathways leading to the cleavage of caspases and downstream cleavage of poly (ADP-ribose) polymerase-1 (PARP-1) [23].

Anti-angiogenic effect

Tumor dissemination via neo-angiogenesis is the hallmark of cancer [25]. Several preclinical studies exhibit the inhibitory effect of UA on angiogenesis and metastasis of cancer cells [6–8]. UA inhibits the angiogenetic potential of non-small cell lung cancer A549 and H460 by decreasing expression of vascular endothelial growth factor (VEGF), metalloproteinase (MMPs) and programmed death ligand-1 (PD-L1) mediated via inhibition of the EGFR/JAK2/STAT3 axis, and that of glioblastoma U251 cells by inhibiting TGF-β signalling [8, 26].

Ani-metastatic effects

Formation of new vasculature aids in the metastasis of cancer cells that disseminate to secondary organs, worsening the disease. UA inhibits the stemness and the metastatic potential of breast cancer cells MDA-MB-231 and MCF-7 cells by decreasing their invasion and migration potential by downregulating epithelial-to-mesenchymal transition (EMT)-markers such as snail, slug, and fibronectin, modulating argonaute 2 (AGO2), and activating SP1/Caveolin-1 signalling [6, 7, 27]. Moreover, UA inhibits the migration capabilities of glioblastoma cells by inhibiting TGF-β-mediated EMT markers and that of intestinal cancer cells via downregulating the RNA levels of metastatic markers such as FN1, CDH2, CTNNB1, and TWIST [26, 28]. UA also downregulated the expression of metalloproteinase (MMP-2) level in colon cancer HCT-116 and SW480 cells to inhibit their migration and invasion capacities [29]. In in vitro studies with human papillary thyroid carcinoma cells, UA inhibits their metastasis via inhibition of the CXCL12/CXCR4/CXCR7 axis, a chemokine signalling pathway essential for migration and invasion of cancer cells [30]. Overall, UA demonstrates its anti-cancerous properties by modulating the major hallmarks of cancer as evidenced by preclinical studies. Table 1 lists all the in vitro and in vivo anti-cancerous studies of UA on different cancers.

Table 1.

Summary of in vitro and in vivo studies on ursolic acid (UA) and its anticancer activities

Cancer type	Model		Mechanism of action	References
	In vitro	in vivo
Lung cancer	(A549, H460 cells)		Inhibition of STAT3/PD-L1signaling pathway (reduced VEGF, MMPs)	Kornel et al. (2022) [5]
Breast cancer	(MDA-MB-231, MCF-7 cells)		Modulation of Argonaute-2, reducing stemness and tumor progression	Liao et al. (2022) [6]
Breast cancer	(MDA-MB-231, MCF-7 cells)		Regulation of EMT transcription factors (Snail, Slug), induction of cell cycle arrest and apoptosis	Mallepogu et al. (2023) [7]
Non-small cell lung cancer	(A549 cells)		Inhibition of STAT3/PD-L1signaling pathway (anti-angiogenic effect)	Kang et al. (2021) [8]
Esophageal cancer	(KYSE-30, KYSE-150 cells)		ROS-mediated autophagy leading to growth and metastasis inhibition	Lee et al. (2020) [14]
Ovarian cancer	(SKOV3 cells)		Induction of apoptosis and G0/G1 arrest via ROS generation and MMP suppression; downregulation of PI3K/Akt pathway	Lin & Ye (2020) [15]
Breast cancer	(MDA-MB-231 cells)		Regulation of Keap1/EGFR/Nrf2 pathway, leading to antiproliferative activity (lower Nrf2)	Zhang et al. (2020) [16]
Ovarian cancer	(SKOV3 cells)		Analysis of molecular mechanisms of UA (transcriptomic and pathway analysis) against ovarian cancer	Zhang et al. (2025) [17]
Melanoma	(WM-266-4 cells)		Antiproliferative activity of rosemary triterpene acids (including UA) on metastatic melanoma cells	Isaković-Vidović et al. (2021) [18]
Oral cancer	(SCC-9, SCC-25 cells)		Induction of apoptosis and autophagy in oral cancer cells	Lin et al. (2019) [19]
Colorectal cancer	(HCT116 cells)		Downregulation of Wnt/β-catenin signaling pathway activity	Zhao et al. (2023) [20, 21]
Gastrointestinal cancer	INT-407 and HCT-116		Role of UA in preventing GI cancers: overview of anti-inflammatory and apoptotic effects (survey of multiple studies)	Chauhan et al. (2024) [22]
Prostate and urogenital cancers	T24, RT4, UMUC3, and 5637		Overview of UA’s effects in vitro and in vivo on prostate/urogenital tumors (anti-proliferative and pro-apoptotic findings)	Kornel et al. (2023) [23]
Breast cancer	(MCF-7 cells)		Modulation of ERK and PI3K/Akt signaling pathways (G1 arrest in breast cancer stem-like cells)	Kim (2021) [24]
Glioblastoma	(U87, U251 cells)		Suppression of TGF-β-mediated EMT and angiogenesis (reduced migratory capacity)	Hei et al. (2024) [26]
Breast cancer	(MDA-MB-231 cells)		Suppression of glycolytic metabolism via SP1/Caveolin-1 signaling (anti-metastatic effect)	Wang et al. (2021) [27]
Intestinal cancer	(HCT116 cells)		Disturbance of ROS homeostasis and regulation of survival gene expression, leading to apoptosis	Rawat & Nayak (2021) [28]
Colon cancer	(HCT116 cells)		Downregulation of ARL4C expression, inhibiting metastatic potential (less migration/invasion)	Zhang et al. (2023) [29]
Papillary thyroid carcinoma	(TPC-1 cells)		Inhibition of CXCL12/CXCR4/CXCR7 axis (via effects on cancer-associated fibroblasts), blocking cell migration and invasion	Cao & He (2022) [30]
Breast cancer	(MCF-7 cells)		Connectivity Map analysis of UA’s anti-tumor mechanism (identifying NF-κB and cell cycle as key targets)	Guo et al. (2020) [31]
Non-small cell lung cancer	A549, H1975, HCC827, and H460		Mechanisms of action and therapeutic potential of pentacyclic triterpenoids (including UA) in NSCLC	Lee et al. (2024) [32]
Cancer cachexia	(C2C12 myotube)	(CT26 tumor-bearing mice)	Inhibition of STAT3signaling pathways, alleviating cancer cachexia (muscle wasting) in vitro and in a cachexia mouse model	Chen et al. (2024) [33]
Colorectal cancer	(HCT116 cells)		Downregulation of TGF-β3 via miR-140-5p, leading to tumor growth inhibition (novel miRNA-mediated effect)	Zhang et al. (2024) [34]
Nasopharyngeal carcinoma	(CNE-1 cells)		Induction of apoptosis through the p53 signaling pathway (network pharmacology + experimental validation)	Wang et al. (2025) [35]
Prostate cancer	(LNCaP cells)		Metabolic rewiring and epigenetic reprogramming (UA demethylates Umor suppressor gene promoters and alters metabolism)	Li et al. (2022) [36]
Prostate cancer	PTEN-knockout PCa models		Regulation of metabolic rewiring and epigenetic changes in PTEN-null prostate cancer; chemo preventive potential of UA	Wang et al. (2022) [37]
Skin cancer		(SKH-1 hairless mice)	Regulation of environmental carcinogen-induced epigenetic and metabolic alterations (UA prevented B[a]P-driven mutations and epigenetic changes)	Sarwar et al. (2024) [38]

Ursolic acid derivatives and structural modifications

In recent years, many researchers have been investigating the possibility of designing novel analogs or derivatives of UA by substituting functional groups at C3, C12-13, and C28 positions of UA to improve oral bioavailability and consequently therapeutic efficacy of UA [31, 32]. For instance, Meng et al. synthesised 19 UA derivatives and found that the cytotoxic effects of derivatives II₄, II₆, III_4, and III₆ were significantly higher than parent UA in human hepatocellular and gastric cancer cells [33]. Gou et al. synthesized a series of derivatives, out of which the derivative UA232 significantly inhibited lung cancer A549 and H460 cells by inducing G0/G1 cell cycle arrest and apoptosis via stimulating the endoplasmic reticulum (ER) stress pathway [31]. In vitro and animal xenograft studies revealed that UA232 also inhibited the proliferation of breast and cervical cancer cells via a similar mechanism, i.e., triggering ER stress and lysosomal dysfunction [34].

Another derivative extracted from Ludwigia hyssopifolia herb also induced apoptosis in throat cancer cells via the same mechanism of triggering ER stress [35]. Wang et al. synthesized novel indolequinone UA derivatives possessing different functional groups showed that compound 6t was most active against breast, cervical and hepatocellular carcinoma cells inhibiting their biological activities via induction of S cell cycle arrest and apoptosis mediated by p-AKT/m-TOR pathway [36]. A UA derivative extracted from Moreover, Silva et al. designed a UA analog by modulating the C-3 moiety containing an amino group, which significantly inhibited the K562 leukemic cells alone and resulted in a synergistic effect when combined with imatinib [37]. Overall, UA derivatives showed better potency and selectivity than UA due to higher aqueous solubility and improved bioavailability.

Molecular targets and signalling pathways evidenced in preclinical studies

UA has the potential to modulate various molecular targets like transcription factor IKK and NF-κB involved in multiple survival and anti-proliferative signalling pathways, such as phosphoinositide 3-Kinase (PI3K)/protein kinase B( Akt)/mTOR, MAPK, STAT3, and Wnt/β-catenin in multiple cancer types [17, 20, 24, 29, 38].

NF-κB and MAPK pathway modulation

For instance, Gou et al. observed that UA inhibits the proliferation of breast cancer MCF-7 cells via significantly modulating the transcription factor IKK/NF-κB, survival pathway RAF/ERK axis [38]. In a similar line, Kim et al. also found that UA inhibits the migration, invasion, and colony-forming potential of MCF-7 cells by inducing G0/G1 cell cycle arrest via downregulating ERK and PI3K/AKT signalling cascade [24].

PI3K/Akt/mTOR and related survival pathways

Furthermore, in vitro studies suggested that UA treatment inhibited the proliferative and migratory potential of colon cancer cells via decreased expression of ARL4C mediated by AKT/mTOR signalling cascade, induced autophagy in oral and ovarian cancer cells via downregulation of Akt/mTOR/NF-κB signalling, ERK, and p38 and PI3K/Akt signalling respectively [17, 19, 29]. UA has altered multiple hallmarks of cancer, including suppression of proliferation, angiogenesis, metastasis, induction of apoptosis, and modulation of inflammatory and immune cascades in non-small cell lung cancer NSCLC) in vitro models via tempering central signalling cascades such as NF-κB, PI3K/Akt, and MAPK [39].

STAT3 and cancer cachexia models

In vivo studies in cancer cachexia mice revealed that UA inhibits cancer cachexia via inhibition of the phosphorylation of NF-κB and STAT3 pathways, and showed a promising therapy for such a multi-organ disorder [40].

Wnt/β-catenin signalling

Moreover, UA also taps into the Wnt/β-catenin signalling pathways, as evidenced by the in vitro studies in colorectal cancer SW620 cells, responsible for inhibition of their proliferation, migration, stemness, and induction of apoptosis [20, 21, 41].

Tumor suppressor and oncogene regulation

Regulation of oncogenes such as mTOR and C-myc and tumor suppressor genes such as p21 and p53 is an effective strategy to inhibit cancer cells. UA has shown the inhibition of multiple cancer types, such as breast, nasopharyngeal carcinoma, and intestinal cancer cells via upregulation of p21 and p53 and downregulation of mTOR, STAT3, C-myc, and BCL-2 in in vitro settings [24, 28, 42].

Epigenetic modulation

In addition to genetic aberrations, epigenetic modifications during the early phase of tumorigenesis lead to cancer development. UA can induce epigenetic reprogramming as evidenced in skin cancer and prostate cancer cells via demethylation of CpG sites in the promoter regions of tumor suppressor genes and reducing the expression of DNA methyltransferases such as DNMT1 and DNMT3a and histone deacetylases [HDACs) [43–45].

Taken together, these preclinical findings suggest that the effect of UA on the genetics and epigenetics targets involved in tumorigenesis can have therapeutic and preventive effects against multiple cancer types. Figure 1 Illustrates the multiple mechanisms of UA anti-tumor action in cancer cells.

Fig. 1.

Mechanistic overview of ursolic acid’s anticancer activities. This schematic illustrates the multifaceted anticancer mechanisms of UA. UA exerts antiproliferative effects by downregulating key signalling pathways such as MAPK, TGF-β, mTOR, AKT, PI3K, NF-κB, STAT3, and EGFR, while upregulating tumor suppressors like p53, p21^WAF1^, and Survivin. It promotes apoptosis via activation of caspases (3, 7, 8, and 9) and induction of p21, p53, and p38. UA induces cell cycle arrest by modulating cyclins and CDKs. Anti-inflammatory effects are mediated through suppression of COX-2 and Nrf2 pathways. It inhibits metastasis and epithelial–mesenchymal transition (EMT) by reducing matrix metalloproteinases (MMPs 2 and 9). UA suppresses angiogenesis by downregulating VEGF signaling. Additionally, it exhibits antioxidant properties through enhancement of SOD and CAT activity. Epigenetic modulation includes inhibition of DNA methylation and histone deacetylation, alongside regulation of miRNAs. Together, UA targets key hallmarks of cancer, including proliferation, apoptosis, metastasis, angiogenesis, inflammation, oxidative stress, and epigenetic dysregulation

Synergistic effects with other therapeutic agents

Combination treatment with UA and chemotherapy, immunotherapy, or radiation therapy could be a new strategy for combating cancer. UA, when combined with platinum agents like oxaliplatin (Oxa), synergistically suppressed the propagation of CRC RKO cells via caspase-mediated induction of apoptosis [9]. Similarly, in the anthracycline class, Hu et al. combined UA with doxorubicin (DOX) and demonstrated that the combination of UA and DOX prompted Akt/Gsk3β inactivation via Hippo signalling axis, resulting in the significant inhibition of CRC cells than DOX alone [46]. Moreover, in the taxance category, UA has been shown to potentiate the effect of paclitaxel and gemcitabine by sensitizing the resistant human esophageal and pancreatic cancer cells by inhibiting Akt/FOXM1 signalling cascade and triggering ER stress, respectively [47, 48]. Beyond chemotherapeutics, Xu et al. fabricated hyaluronic acid (HA)-modified UA/(astragaloside IV (AS-IV))-loaded polydopamine (PDA) nanomedicine (UA/(AS-IV)@PDA-HA). This nanomedicine signifies the combination of natural compounds UA with AS-IV with chemo, photothermal, and immuno-therapy. This combination strategy inhibited the growth and dissemination of NSCLC in vitro and in vivo [49]. Thus, these studies suggested that the combination therapy of UA with anticancer therapy might be more effective than anticancer or UA therapy alone Fig. 2.

Fig. 2.

Synergistic anticancer mechanisms of ursolic acid in combination with therapeutic agents. This schematic illustrates the synergistic interactions between ursolic acid and various anticancer agents, targeting different cancer types through distinct molecular pathways. CRC Colorectal cancer, NSCLC non-small cell lung cancer

Formulation strategies to enhance bioavailability

To enhance the bioavailability of UA, several formulation strategies have been explored [50]. Lipid carriers like liposomes, solid lipid nanoparticles (SLNs), nanophytoliposomes, and niosomes have been explored for UA. Poudel et al. (2020) developed UA-PLL-HA.P, a dual stimuli-responsive nanophytoliposome, where UA is encapsulated in a liposomal core decorated with hyaluronic acid (HA) [51]. This system is pH and enzyme-sensitive: in the slightly acidic, hyaluronidase-rich tumor microenvironment, it releases UA preferentially. HA provides active targeting by binding CD44 receptors often overexpressed on cancer cells, thus increasing uptake [51]. Polymeric delivery systems can improve UA’s solubility and provide controlled release. For instance, Antonio et al. formulated chitosan-(CS) modified poly (lactic acid) (PLA) nanoparticles containing UA loaded with UA to enhance oral delivery [52]. This system showed increased oral bioavailability of UA in rats (several-fold higher AUC than free UA). The chitosan coating muco-adheres in the gut and facilitates UA transport across the intestinal epithelium. Chitosan UA-loaded hybrid Poly (lactic-co-glycolic acid)/lipid nanoparticles, combine a polymer core with a lipid shell to leverage the stability of polymers and the biomimicry of lipids. Markowski et al. (2022) created such a hybrid NP for pancreatic ductal adenocarcinoma, achieving greater tumor cell uptake and cytotoxicity compared to UA in solution [53]. HA-modified liposomes and self-assembled folate-modified pectin nanoparticle for loading ursolic acid (HCPT@F-Pt-PU NPs) offer active tumor targeting via CD44 and folate receptors, respectively [54]. Inorganic nanoparticles can impart unique functionalities like magnetic targeting. Ghasemzadeh et al. (2022) developed a UA loaded β-cyclodextrin/folic acid/Fe3O4 nanocomplex [55]. UA was complexed with β-cyclodextrin to improve solubility, folic acid provided active tumor targeting (folate receptor binding), and Fe₃O₄ rendered the particles magnetically responsive. Other researchers have been investigating different methods, such as using a simple redox-sensitive UA polymeric prodrug for resolving UA release [56], UA-loaded transniosomes nanogel for dermal delivery for skin cancer [57], a hydrogel drug delivery system for multi-targeted therapy of lung cancer [58], pH-responsive hydrogel for improved oral delivery [59]. Many of the nano-formulations exploit the enhanced permeability and retention (EPR) effect (passive targeting), wherein nanoparticles naturally accumulate in tumors due to leaky vasculature and poor lymphatic drainage (For example: UA-loaded nanoparticles PLGA/lipid NPs, SLNs) benefit from EPR). While, active targeting uses ligands (folate, antibodies, peptides, HA, etc.) to bind to tumor-specific receptors. Overall, UA can be delivered orally conjugated with nanoparticles, niosomes, liposomes, and hydrogels, etc., with improved stability, bioavailability, kinetics, and efficacy for multiple cancer types (Table 2).

Table 2.

Formulation strategies to enhance the bioavailability of ursolic acid (UA)

Formulation type	Carrier/system name	Main components	Target / indication	Key features / mechanism	References
Nanophytoliposome	UA-PLL-HA.P	Dual stimuli-responsive liposome + HA (targeting)	General solid tumor therapy (e.g., breast)	Targeted delivery (HA-CD44 binding) and dual stimulus response (releases UA in acidic, enzyme-rich tumor microenvironment)	Poudel et al. 2020 [51]
Polymeric nanoparticles	CS-PLA NPs	Chitosan-coated poly(lactic acid) nanoparticles	Oral delivery improvement (various cancers)	Mucoadhesive protection in GI tract, enhanced intestinal uptake, significantly increased oral bioavailability in vivo	Antonio et al. 2021 [52]
Hybrid nanoparticles	PLGA/Lipid NPs	Poly(lactic-co-glycolic acid) core + lipid shell	Pancreatic ductal adenocarcinoma	Long-circulating, stable NP with EPR effect, improved tumor cell uptake and cytotoxic efficacy against PDAC cells	Markowski et al. 2022 [53]
Self-assembled NP	HCPT@F-Pt-PU NPs	Pectin-PEG polymer NP modified with folic acid (FA)	Intracellular delivery to folate-receptor positive tumors	Folate-targeted NP (active uptake), improved cellular internalization and intracellular UA release, enhances chemotherapy inside cancer cells	Liu et al. 2021 [54]
Nanocomplex	β-CD/FA/Fe₃O₄	β-cyclodextrin-UA inclusion complex with folic acid and magnetite (Fe₃O₄)	Magnetic tumor targeting (multiple types)	Magnetically guided targeting using Fe₃O₄ (external magnet draws particles to tumor) + folate receptor targeting for uptake; dramatically increased tumor localization of UA	Ghasemzadeh et al. 2022 [55]
Polymeric prodrug	Redox-sensitive prodrug	UA covalently linked to a redox-responsive polymer (disulfide bond)	Osteosarcoma (and other tumors with high GSH)	Controlled UA release in high-GSH tumor environment (disulfide bond cleavage), improved solubility, and selective toxicity in tumor cells	Fu et al. 2021 [56]
TransniosomesNanogel	UA-loaded nanogel	Transfersome (ultra-deformable niosome) in a hydrogel matrix	Skin cancer (topical delivery)	Topical formulation with enhanced skin permeation, allows UA to penetrate to deeper skin layers; increased local concentration, reduced systemic exposure	Makeen et al. 2023 [57]
Hydrogel system	UA + Cisplatin hydrogel	Biocompatible hydrogel co-loading UA and cisplatin	Lung cancer (localized therapy)	Injectable depot for sustained co-delivery; provides multi-target therapy (DNA damage by cisplatin + UA’s pathway inhibition), UA also inhibits TMEM16A to curb metastasis	Li et al. 2024 [58]
pH-responsive hydrogel	pH-sensitive hydrogel	Smart polymer matrix (e.g., with carboxylate groups) that encapsulates UA	Oral delivery (protect UA through stomach, release in intestine)	Protects UA in stomach acid, releases in neutral/acidic pH of GI tract or tumor; improves oral stability and absorption, better shelf-stability of UA	Gutierrez et al. 2024 [59]

Clinical studies and human trials

The efficacy and safety studies of UA in clinical subjects are extremely limited. Therefore, Qian et al. conducted multiple-dose pharmacokinetics and efficacy studies of UA liposome (UAL) in subjects with advanced tumors. 21 subjects were divided into cohorts of 56, 74, and 98 mg/m²,and UAL was administered for 14 days of a 21-treatment cycle. UAL was well tolerated, with 60% of the subjects showing improved remission rates, no adverse events, and accumulation of UAL in the body [60]. Two phase 1 studies assessed the safety and pharmacokinetics of UAL administered parenterally in healthy individuals and subjects with advanced solid tumors. Wang et al. conducted a Phase I clinical trial of ursolic acid liposomes (ChiCTR-TRC-11001806), administering single escalating doses (up to 98 mg/m²) to healthy volunteers and cancer patients [61]. Zhu et al. carried out a similar Phase I study (ClinicalTrials.gov ID: NCT02126449), evaluating UA liposomes in healthy individuals and patients with advanced solid tumors [62]. Both studies showed dose-proportional kinetics up to 98 mg/m², with manageable toxicities. The maximum tolerated dose was 98 mg/m²with dose-limiting toxicities including liver toxicity and stomach issues [61, 62]. No UA accumulation with linear PK profile was seen. While these Phase I trials were not designed to demonstrate efficacy, anecdotally some patients with advanced cancers in the trials had stable disease for a few months, hinting at UA’s activity. However, no Phase II or III trials have been completed yet to test UA’s efficacy in a larger patient population or in a specific cancer type. however, more clinical studies are warranted for further validation.

Challenges and limitations

UA is a highly hydrophobic compound that exhibits poor absorption in the gastrointestinal tract, resulting in its low oral bioavailability. From a phytochemical standpoint, UA’s low aqueous solubility stems from its rigid pentacyclic triterpenoid structure and limited polar functional groups, which also hinder formulation versatility. Rapid first-pass metabolism and clearance from the body further limit its exposure in the bloodstream. Studies indicate that the bioavailability of UA remains very low unless formulated as advanced drug delivery systems [12]. Since the major anticancer evidence comes from preclinical studies and early-phase clinical trials, UA’s therapeutic window is not well-defined. Further, the toxicological studies demonstrate that UA is well tolerated mostly in preclinical models, however, higher doses of UA might adversely affect the hepatic and gastrointestinal regions of the body, especially when administered in clinical settings. Another obstacle is the translational hurdle from lab to clinical practice, since studies utilizing cancer cell lines cannot mimic the tumor microenvironment, pharmacodynamics, and complexities in patients. Formulation-related challenges such as low encapsulation efficiency, burst drug release, and instability of delivery systems under physiological conditions also hinder consistent delivery to tumor sites. Moreover, disparity in the extraction, purification, and formulation practice by different researchers results in inconsistencies in the preparation of dosing and outcomes, obstructing standardization [63]. Therefore, Therefore, a lack of harmonized phytochemical processing protocols and optimized formulation platforms remains a major barrier. standardization in UA preparation and thorough clinical trials are prerequisites for establishing UAs as clinically validated anticancer agents.

Future perspectives and research directions

Research should mainly focus on bridging the gap between preclinical and clinical studies. Since there are limited clinical studies of this promising anticancer agent, it is necessary to direct the research in a way that addresses the key limitations of this compound. Moreover, safety concerns, pharmacokinetic challenges, and tumor specificity restrict its widespread application. For this purpose, key directions include: (1) Thorough randomised late-phase clinical trials in specific tumor types to assess UA’s efficacy, safety, and therapeutic window in patients. (2) Targeted delivery via antibody or ligand-conjugated UA nanoparticles to guide the drug to targeted tumor tissues minimizing systemic exposure. (3) Combination therapies such as meticulous exploration of UA with immunotherapy or targeted therapy to enhance synergistic efficacy; (4) identification of genetic or molecular tumor profiles that can envisage the response of UA against them so that personalised treatment can be curated. (5) Monitoring the effect of UA by evaluating established molecular identifiers such as transcription, epigenetic factors, etc. Additionally, studies should focus on developing and designing UA derivatives with better drug-like ability and improved pharmacokinetics. In parallel, efforts should focus on standardizing extraction, purification, and formulation practices across research groups to enable reproducibility and clinical comparability. Overall, a coordinated, multidisciplinary approach is needed to transition UA from promising phytochemical to clinically approved anticancer therapy.

Conclusion

UA is a natural triterpenoid with multidimensional antineoplastic assets, including antioxidant, anti-inflammatory, pro-apoptotic, anti-angiogenic, and anti-metastatic activities. It tempers key transcription factors, signalling pathways such as survival and epigenetic pathways, etc., and synergises with anticancer therapies such as targeted or immunotherapy. Preclinical findings consistently show that UA inhibits tumor progression and development in vitro and in vivo. Advanced formulation strategies, including nanoencapsulation, are utilised by various research groups to overcome UA’s bioavailability challenge. Although more clinical studies are being conducted, the safety profile looks acceptable. In summary, currently UA represents a potential complementary anticancer compound; however, with continuous research on UA’s mode of action, improved drug delivery system, and rigorous clinical trials will determine its future role in cancer therapy.

Author contributions

Amol Patil: Writing – review & editing, investigation, conceptualization. Durgacharan Bhagwat: Writing – review & editing, Investigation, conceptualization, project administration, supervision.

Funding

Not applicable. This study did not receive any funding or financial support.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable. This article is a review and does not involve any studies with human participants or animals performed by the authors.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.