The improvement effect of ellagic acid and urolithins on metabolic diseases: Pharmacology and mechanism

Ying-Hao Wang; Wen-Yuan Peng; Chun-Feng Li; Yi-Long Wu; Jun Sheng; Cheng-Ting Zi; Xiao-Yun Wu

doi:10.26599/FMH.2025.9420058

| Sign up

PDF (9.3 MB)

Cite

EndNote(RIS) BibTeX

Collect

Submit Manuscript

Show Outline

Figures (8)

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Tables (2)

Table 1

Table 2

Open Access | Online First

The improvement effect of ellagic acid and urolithins on metabolic diseases: Pharmacology and mechanism

Ying-Hao Wang^{¹^,²^,³^,^†}, Wen-Yuan Peng^{¹^,²^,³^,^†}, Chun-Feng Li^{¹^,²^,³}, Yi-Long Wu^{¹^,³}, Jun Sheng^²(), Cheng-Ting Zi^{¹^,²^,³}(), Xiao-Yun Wu^{¹^,²^,³}()

1Research Center for Agricultural Chemistry, College of Science, Yunnan Agricultural University, Kunming 650210, China

2Key Laboratory of Pu-erh Tea Science, Ministry of Education, College of Food Science and Technology, Yunnan Agricultural University, Kunming 650201, China

3Institute of Biofabrication Research, College of Science, Yunnan Agricultural University, Kunming 650201, China

^†Ying-Hao Wang and Wen-Yuan Peng contributed equally to this work.

Show Author Information

Highlights

(1) Discovery that ellagic acid exists in various natural plants.

(2) Metabolic pathways of ellagic acid in colonic microbiota.

(3) Summarized the roles of ellagic acid and urolithin in metabolic diseases.

(4) Provide an important reference for exploring the medicinal value of ellagic acid.

Graphical Abstract

View original image Download original image

Ellagic acid (EA) is a polyphenolic compound with multiple biological activities. Most of the EA enters the colon and is mainly metabolized by the colonic microbiota to form urolithin. The biological activity of EA and its metabolites is related to the occurrence of metabolic diseases. This article summarized the beneficial effects of EA and urolithin on type 2 diabetes, obesity, atherosclerosis, nonalcoholic fatty liver disease, hypertension and hyperuricemia and their related signaling pathways.

Abstract

Epidemiological studies have demonstrated that a range of metabolic diseases, particularly type 2 diabetes and obesity, have reached epidemic proportions. These chronic conditions not only diminish the equality of life for individuals but also impose significant financial burdens on families and healthcare systems. While various therapeutic medications can effectively manage the progression of these diseases, they often come with adverse side effects. In contrast, natural products and their metabolites, such as ellagic acid (EA) and urolithins derived from a variety of plant species, have gained attention for their wide-ranging biological activities, diverse classes, and minimal side effects. Emerging research suggests that EA and urolithins may offer promising therapeutic effects in the treatment of metabolic disorders. This review aims to provide a comprehensive overview of the therapeutic effects and associated signaling pathways of EA and its metabolite urolithins in various metabolic diseases, offering valuable insights for their clinical applications and the potential development of novel food and medicine homologous therapies.

Keywords

ellagic acid urolithins metabolic diseases therapeutic effects

References

[1]

Saklayen, M. G. The global epidemic of the metabolic syndrome. Current Hypertension Reports, 2018, 20: 12. https://doi.org/10.1007/s11906-018-0812-z

	Plant species	Part	EA content (mg /kg)	Ref.
a represents dry weight, b represents fresh weight.
Nuts	Carya illinoinensis (Wangenh.) K. Koch	Meat	330 ^a	[45]
	Vigna angularis (Willd.) Ohwi & H. Ohashi	Adzuki bean	89.6 ^a	[46]
	Vigna unguiculata (L.) Walp.	Mottled cowpea	181 ^a	[46]
	Phaseolus vulgaris L.	Speckled kidney bean	95.8-183 ^a	[46]
	Pisum sativum L.	Green pea	96.8 ^a	[46]
	Glycine max (L. )Merr.	Black soy bean	456 ^a	[46]
	Glycine max (L.) Merr.	Yellow soy bean	489 ^a	[46]
	Juglans nigra Linn.	meat	590 ^b	[45]
Fruits	Myrciaria dubia (H.B.K.) McVaugh	Pulp	258.5 ^a	[47]
		Flours	5,657 ^a	[47]
	Punica granatum L.	Arils	700 ^a	[48]
		Mesocarp	38,700 ^a	[48]
		Peels	5,150±190 ^a	[49]
		Seed coat	14,430±210 ^a	[50]
	Rosa L. species	Rosehip	1,096 ^b	[51]
	Arctic bramble (arctic raspberry)	Berries	3,900 ^b	[52]
	Rubus chamaemorus L.	Berries	3,151 ^b	[51]
	Rubus idaeus L.	Red raspberries	10 ^b	[53]
		Rasp berry	1,500-3,309 ^b	[51]
		Boysen berry	1,684-4,960 ^a	[54, 55]
	Rubus ursinus	Blackberry	1,500 ^a	[45]
	Terminalia Ferdinandiana	Kakadu plum	8,796 ^a	[54, 56] [57]
	Vaccinium macrocarpon Ait.	Cranberry	120 ^a	[45]
	Muscadinia rotundifolia (Michx.)	Fruit	360-912 ^b	[58, 59]
	Castanea sativa Mill.	Leaf	340-500 ^a	[59]
		Bur	1,410-3,210 ^a	[59]
		Outer shell	240-900 ^a	[59]
		Inner shell	800-1,370 ^a	[59]
	Fragaria × ananassa Duch.	Fruit	48-55 ^a	[60]
	Hippophae rhamnoides L.	Fruit	10 ^b	[45]
	Caryocar brasiliense Cambess.	Peel flours	5,094.7-16,306.6 ^a	[61]
	Cucurbita pepo L.	Fruit	10.28-36.66 ^b	[62]
	Dimocarpus longan Lour.	Seed	8,130-1,2650 ^a	[63]
	Vitis rotundifolia Michx.	Peel flours	8-162 ^b	[64]
Tea	Camellia taliensis (W. W. Sm.) Melch.	Leaf	15-446^a	[65]
Tree	Alternanthera sessilis (L. ) R. Br. Ex DC.	Plant material	30,072.6 ^a	[66]
	Alnus cremastogyne Burkill.	Acorns	15,931.3-21,719 ^a	[67]
	Eucalyptus globulus Labill.	Fruit	-	[68]
	Rhus chinensis Mill.	Gall	-	[69]
	Trapa natans L.	Pericarp	-	[70]
Vegetable	Geum japonicum Thunb.	Whole plants	3,064.1-4,026.6 ^a	[71]
	Amaranthus tricolor L.	Leaf	1.24-6.23 ^b	[72]

Diseases		Activity/mechanism(s) of action	Cell lines/model	Dose	Application (route of amelioration)	Reference
T2DM	Promote glucose uptake and insulin secretion	Alter lipase, amylase, IL-6, PCNA and TNF- α expression and enhanced islet cell renewal, insulin, and immunoreactivities	Streptozotocin-induced diabetic rats	50 mg/kg	In vivo (Oral gavage)	[83]
		Increase insulin expression of β cells and improve oxidation stress	Streptozotocin-induced diabetic rats	50 mg/kg	In vivo (Oral gavage)	[84]
		Inhibit beta-cell apoptosis and stimulation of insulin production	HFD with streptozotocin-induced diabetic rats	10 mg/kg	In vivo (Intraperitoneal Injection)	[85]
		Enhance ERK1/2 activation	INS-1 cells	20/100 µmol/L	In vitro	[86]
		Promotes mitochondrial biogenesis and mitochondrial respiration, improving whole-body insulin sensitivity	HFD mice	20 µg/day	In vivo (Intraperitoneal Injection)	[87]
		Prevents pancreatic β-cell apoptosis by inducing activation of SQSTM1/p62 and LC3II autophagy	Mouse islet β-cells; Streptozotocin-induced diabetic mice	11.5 µg/mL; 50 mg/kg	In vitro; In vivo (Oral gavage)	[88]
		Activate PI3K/AKT signaling pathway and AMPK signaling pathway	L6 myotubes; KK-A^y/TaJcl mice	100 µmol/L; 100 mg/kg	In vitro; In vivo (Oral gavage)	[89]
	Improve insulin resistance	KEAP1-Nrf2 activation mediated by miR-223	HepG2 cells	15/30 µmol/L	In vitro	[29]
		Reductions in p47-phox and HIF-&alpha, upregulation of NRF2 and enhancement of the Akt signaling pathway	Goto Kakizaki rats	50 mg/kg	In vivo (Oral gavage)	[90]
		Decreased the levels of TNF-α, IL-6 and CRP, increased the levels of 11β-HSD2 and PPARα-TRB3-AKT2-p-FOXO1-GLUT2 signal	Gestational diabetes mellitus rats	50/150/300 mg/kg	In vivo (Oral gavage)	[35]
		Improve mitochondrial function	High fat/high sucrose diet mice	diet supplemented with 0.1%	In vivo (Oral administration)	[91]
	Inhibit inflammation and oxidative stress	Increased TAC and decreased MDA and TOS level	Streptozotocin-induced diabetic rats	25/50 mg/kg	In vivo (Oral gavage)	[97]
		Inhibit MGB1-TLR4-NF-кB pathway	Streptozotocin-induced diabetic mice	50/100/150 mg/kg	In vivo (Oral gavage)	[98]
		Lower renal pathology and suppress TGF-β and fibronectin expressions, reduce the serum levels of pro-inflammatory cytokines,IL-1β,IL-6 and TNF-α,induce activation of NF-κB and pro-inflammatory cytokine synthesis	Rat NRK 52E proximal tubular epithelial cells; HFD with streptozotocin-induced diabetic rats	5 µmol/L; 20/40/60/80/100 mg/kg	In vitro; In vivo (Oral gavage)	[99]
		Activates AMPK and autophagy to inhibit endoplasmic reticulum stress associated TXNIP/NLRP3/IL-1β signal pathway	MIN6 pancreatic β cells; HFD with streptozotocin-induced diabetic mice	50 µmol/L; 50 mg/kg	In vitro; In vivo (Oral gavage)	[100]
Obesity	Inhibit fat synthesis and accumulation	Reduction of Cyclin A protein expression and Rb phosphorylation, blocking of G1/S phase transition	3T3-L1 cells	10/15/20 µmol/L	In vitro	[105]
		Reduced PPARγ and C/EBPα, arresting cells at the G0/G1 phase	3T3-L1 cells	5/25/50 µmol/L	In vitro	[106]
		Elevated the levels of SIRT1, p-AMPK, and PPAR-α and reduced SREBP-1c level	Young control, old control rats		In vivo	[107]
		Downregulated the expression of LXRα and SREBP1c, upregulating PPARα expression, decreased the expression of PERK and IRE1α	HFD rats	2.5 mg/kg	In vivo (Intraperitoneal Injection)	[108]
	Promote WAT browning and BAT thermogenesis	Promote beige differentiation/activation	3T3-L1 cells	100 µmol/L	In vitro	[111]
	Promote WAT browning and BAT thermogenesis	Suppress white adipocyte maintaining genes and promoting expression of key thermogenic genes	HFD rats	10/30 mg/kg	In vivo	[112]
		Induce beige remodeling of WAT by regulating the mitochondrial dynamics and SIRT3	3T3-L1/SVF cells; Cold-exposed mouse	25 µmol/L; 20 mg/kg	In vitro; In vivo (Oral administration)	[113]
		elevation of triiodothyronine (T3) levels in BAT	HFD mice	30 mg/kg	In vivo (Oral gavage)	[114]
Atherosclerosis	Inhibit inflammation	Increased adiponectin levels, decreased levels of inflammation markers, inhibited MCP-1	HFD apolipoprotein E-deficient mice		In vivo	[118]
		inhibiting NADPH oxidase-induced overproduction of superoxide, down-regulating iNOS	Human umbilical vein endothelial cells	5/10/15/20 µmol/L	In vitro	[119]
		Reduce the adhesion of monocytes and sVCAM-1 and IL-6	THP-1 monocytes to human umbilical vein endothelial cells	10 µmol/L	In vitro	[120]
		Alleviate endothelial dysfunction induced by ox-LDL partially through modulating miR-27 expression and ERK/PPAR-γ pathway	Human artery endothelial cells	0.5/2.5/5 µmol/L	In vitro	[121]
	Inhibit cholesterol accumulation	Anti-oxidant and modulate the PI3K/Akt/eNOS signaling pathway	Human umbilical vein endothelial cells	5/10/15/20 µmol/L	In vitro	[123]
		Improved RCT functionality and HDL function	High-cholesterol paigen diet induce hypercholesterolemia mice	10 mg/kg	In vivo (Oral gavage)	[124]
		Suppressed the aortic level of 8-(OH) dG and the expression of caspase-8, caspase-9 and Fas ligand	High fat and cholesterol diet rabbits	diet supplemented with 1%	In vivo (Oral administration)	[125]
		Upregulation of SR-BI expression and inhibition of p-ERK1/2 levels	high cholesterol diet supplemented with Vitamin D3 rats	3 mg/kg	In vivo (Oral administration)	[126]
		Regulating the miRNA-33 expression and interaction with the ERK/AMPKα/SREBP1 signaling pathway	RAW264.7 cells	50 µg/mL	In vitro	[127]
	Inhibit oxidative stress	Increased Nrf2 and HO-1 expression	HFD apolipoprotein E-deficient mice	30 mg/kg	In vivo (Oral gavage)	[130]
		Blocking proliferation of vascular smooth muscle cells	Rat aortic smooth muscle cells; Streptozotocin-induced diabetic rats	25 µmol/L; diet supplemented with 2%	In vitro; In vivo (Oral administration)	[131]
		activated eNOS expression	Human aortic endothelial cells	15 µmol/L	In vitro	[132]
NAFLD		Improved liver and mitochondrial damage, oxidative stress index, liver function markers and lipid levels	HFD mice		In vivo	[136]
		Enhance the antioxidant enzyme activities, elevating adiponectin, PPAR-α and lowering SREBP-1c	HFD rats		In vivo	[137]
		Inhibit pyruvate kinase（PKL）	Structure-activity analysis			[138, 141]
		Reduced inflammatory levels of ROS, TNF-a, and IL-6, and activated the AMPK signaling pathway to enhance the expression of genes such as CPT1a and CPT1b	Streptozotocin-induced diabetic rats	50 mg/kg	In vivo (Oral gavage)	[139]
		Suppressing lipid metabolic reprogramming and triggering lipophagy	HepG2 cells and primary hepatocytes; High-fructose-fed mice	10/20/40 µmol/L; 50/100 mg/kg	In vitro; In vivo (Oral administration)	[156]
Gout and hyperuricemia		Inhibit of NLRP3 and XOD			In vitro	[144]
		Inhibits the activity of XO	AML12 hepatocytes; Purine bodies-induced hyperuricemia mice	100 µmol/L; 100/300 mg/kg; 80/240 mg/kg	In vitro; In vivo (Oral gavage)	[146, 148]
		Activation of CTRP3 and inhibition of ACL activities	HFD rats	15 mg/kg	In vivo (Oral gavage)	[147]
Hypertension		Improving nitric oxide bioavailability, attenuated plasmatic alkaline phosphatase activity, calcium content	N_ω-Nitro-L-arginine methyl ester hydrochloride induced hypertension rats	10/30 mg/kg	In vivo (Oral gavage)	[153]
		Reduce NADPH oxidase subunit p47phox expression	N_ω-Nitro-L-arginine methyl ester hydrochloride induced hypertension rats	7.5/15 mg/kg	In vivo (Oral administration)	[154]
		Endothelial nitric oxide synthase activation, stimulating the Superoxide Dismutase 2-catalase pathway	Ovariectomized spontaneously hypertensive rats	10 mg/kg	In vivo (Oral administration)	[155]