Hesperetin is an effective antioxidant and anti-inflammatory agent. Hesperetin conferred neuroprotection by regulating the TLR4/NF-κB (Toll-like receptor-4) signaling pathway against the detrimental effects of LPS(lipopolysaccharide) [3]. Hesperetin (HET) and naringenin (NGR) are flavanones found in citrus (oranges and grapefruit) and Aurantii Fructus Immaturus. HET and NGR displayed broad-spectrum inhibition against human UGTs. HET exhibited strong inhibitory effects on UGT1A1, 1A3 and 1A9 (both IC50 and Ki values lower than 10 µM) [4]. Hesperetin interacts with different types of proteins involving hydrogen bonds, pi-pi effects, pi-cation bonding and pi-sigma interactions with varying binding energies. Hesperetin exhibits drug-like properties which projects its potential as a therapeutic option for CHIKV infection[5]. Preadministration of Hesperetin (40 mg/kg b.w., oral) significantly attenuated the Cd-induced (cadmium) oxidative stress and mitochondrial dysfunction, restored the antioxidant and membrane-bound enzyme activities and decreased apoptosis in the brain of rats[6]. Hesperetin (200 mg/kg) attenuates Con A-induced hepatocyte apoptosis and hepatic Nos2 (iNOS) expression in mice. Hesperetin blocked bile acid-induced apoptosis and cytokine-induced inflammation in rat hepatocytes[7].
Hesperetin/橙皮素 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HeLa cells
100 µM
1 hour
To study the effect of hesperetin on the binding of TGF-β1 to TβRII, results showed that hesperetin reduced the probability of ligand-receptor binding.
Eur J Med Chem. 2012 Dec;58:390-5.
Lewis lung carcinoma (LLC) cells
30 µM
1 hour
To evaluate the protective effect of hesperetin against acrolein-induced toxicity in LLC cells. Results showed that hesperetin pretreatment significantly increased cell viability and reduced the expression of apoptosis marker proteins (e.g., cleaved caspase-3, cleaved PARP, cytochrome C, and p-p53).
Redox Rep. 2018 Dec;23(1):188-193.
HeLa cells
100 µM
24 hours
To study the effect of hesperetin on TGF-β1-induced cell migration, results showed that hesperetin inhibited cell migration capacity.
Eur J Med Chem. 2012 Dec;58:390-5.
SH-SY5Y AßPPwt cells
0.01–10 µM
24 hours
To evaluate the antioxidant capacity and changes in ATP levels of hesperetin nanocrystals in an Alzheimer’s disease cell model. Results showed that hesperetin nanocrystals significantly increased ATP levels, with more pronounced effects observed in 170 nm nanocrystals.
Drug Deliv Transl Res. 2021 Apr;11(2):659-674.
HEK293-CISD2 reporter cells
10-30 µM
24 hours
Screening for CISD2 activators via luciferase reporter assay, hesperetin enhances CISD2 expression
J Biomed Sci. 2022 Jul 24;29(1):53.
Human aortic valve interstitial cells (VICs)
3 µM
24 hours
Hesperetin pretreatment inhibited LPS-induced NF-κB inflammatory cytokine secretion and osteogenic factor expression, reduced ROS production and apoptosis, and abrogated LPS-mediated injury to the mitochondrial membrane potential and the decline in antioxidant levels in VICs.
Antioxidants (Basel). 2022 Oct 24;11(11):2093.
SH-SY5Y-MOCK cells
0.01 to 10 µM
24 hours
The effects of HstN on SY5Y-MOCK control cells were relatively small. HstP had almost no effect on both cell lines.
Antioxidants (Basel). 2021 Jun 23;10(7):1003.
SH-SY5Y-APP695 cells
0.01 to 10 µM
24 hours
HstN significantly reduced mitochondrial dysfunction: ATP levels and respiratory chain complex activity significantly increased. Gene expression levels of RCC I, IV, and V were significantly upregulated. HstP had almost no effect on both cell lines.
Antioxidants (Basel). 2021 Jun 23;10(7):1003.
AGS cells
0, 6.25, 12.5, 25, 50 µM
24 hours
To evaluate the effect of hesperetin on the translocation of CagA and VacA proteins into AGS cells infected with H. pylori. Results showed that hesperetin treatment significantly reduced the translocation of CagA and VacA proteins.
Int J Mol Sci. 2021 Sep 17;22(18):10035.
THP-1 macrophages
0–40 μg/mL
24 hours
Evaluate the inhibitory effect of Hesperetin on Spike S1-induced inflammatory responses, significantly reducing the release of IL-6, IL-1β, and IL-18
Moore Inhibits SARS-CoV-2 Spike Protein S1 Subunit-Induced NLRP3 Inflammasome in A549 Lung Cells via Modulation of the Akt/MAPK/AP-1 Pathway. Int J Mol Sci.
A549 lung cells
0–40 μg/mL
24 hours
Evaluate the inhibitory effect of Hesperetin on Spike S1-induced inflammatory responses, significantly reducing the release of IL-6, IL-1β, and IL-18
Moore Inhibits SARS-CoV-2 Spike Protein S1 Subunit-Induced NLRP3 Inflammasome in A549 Lung Cells via Modulation of the Akt/MAPK/AP-1 Pathway. Int J Mol Sci.
HT-22 cells
50 µM
24 hours
To evaluate the effect of hesperetin on LPS-induced cytotoxicity and ROS/LPO. Hesperetin significantly reduced LPS-induced cytotoxicity and ROS/LPO levels.
Nutrients. 2019 Mar 17;11(3):648.
BV2 cells
50 µM
24 hours
To evaluate the effect of hesperetin on LPS-induced TLR4 and Iba-1 protein expression. Hesperetin significantly reduced LPS-induced TLR4 and Iba-1 protein levels.
Nutrients. 2019 Mar 17;11(3):648.
HEK001-shCISD2 cells
10 µM
48 hours
In CISD2 knockdown cells, hesperetin loses its beneficial effects on mitochondrial function and antioxidant capacity
J Biomed Sci. 2024 Jan 23;31(1):15.
HEK001 human keratinocytes
10 µM
48 hours
Enhances mitochondrial function and protects against ROS-induced oxidative stress via increased CISD2 expression
J Biomed Sci. 2024 Jan 23;31(1):15.
H226 cells
75, 150, 300 µM
48 hours
To evaluate the effect of HST on the viability of H226 cells, results showed that HST inhibited cell viability in a concentration- and time-dependent manner, induced G2/M phase cell cycle arrest and apoptosis.
Int J Mol Med. 2025 May;55(5):77.
H1703 cells
37.5, 75, 150 µM
48 hours
To evaluate the effect of HST on the viability of H1703 cells, results showed that HST inhibited cell viability in a concentration- and time-dependent manner, induced G2/M phase cell cycle arrest and apoptosis.
Int J Mol Med. 2025 May;55(5):77.
HepG2 cells
20 µM and 40 µM
4-hours pretreatment followed by 24-hours PA stimulation
To investigate the inhibitory effect of hesperetin on PA-induced cell death and NLRP3 inflammasome activation in HepG2 cells. Results showed that hesperetin significantly increased cell viability, reduced cell death, and inhibited PA-induced IL-1β and IL-18 mRNA expression and NLRP3 and caspase-1 protein expression.
J Agric Food Chem. 2024 Jun 12;72(23):13039-13053.
A549/DDP cells
0.6, 1.25, 2.5, 5, 10 µM
72 hours
Assessed the toxic effects of hesperetin on A549/DDP cells and its synergistic effect with cisplatin; concentrations ≥2.5 µM significantly enhanced the cytotoxicity of DDP
Int J Mol Med. 2020 Apr;45(4):1213-1224.
Human lung adenocarcinoma A549 cells
0.6, 1.25, 2.5, 5, 10, 20, 40, 80, 160 µM
72 hours
Evaluated the toxic effects of hesperetin on A549 cells; low concentrations (<5 µM) had no significant effect, while higher concentrations (>20 µM) significantly inhibited cell proliferation
Int J Mol Med. 2020 Apr;45(4):1213-1224.
Hesperetin/橙皮素 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Naturally aged mouse model
Oral
100 mg/kg/day
Continued for 3-6 months
Hesperetin extends healthspan, ameliorates age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence
Evaluated the inhibitory effect of hesperetin on A549/DDP cell growth in vivo; hesperetin pretreatment significantly inhibited tumor growth
Int J Mol Med. 2020 Apr;45(4):1213-1224.
BALB/c nude mice
H226 xenograft model
Intraperitoneal injection
30, 60, 90 mg/kg
Once every 2 days for 28 days
To evaluate the anti-tumor effect of HST on H226 xenograft tumors, results showed that HST significantly inhibited tumor growth without apparent toxic side effects.
Int J Mol Med. 2025 May;55(5):77.
C57BL/6 mice
Direct wire injury (DWI)-induced aortic valve stenosis model
Oral gavage
50 mg/kg
Once daily for 7 days
Hesperetin supplementation protected mice from wire-injury-induced aortic valve stenosis; in vivo, hesperetin corrected dysfunctional mitochondria by activating the Nrf2-ARE signaling pathway.
Antioxidants (Basel). 2022 Oct 24;11(11):2093.
C57BL/6N mice
LPS-induced neuroinflammation model
Oral gavage
50 mg/kg
Daily for a total of five weeks
To evaluate the effect of hesperetin on LPS-induced neuroinflammation, oxidative stress, and memory impairments. Hesperetin significantly reduced LPS-induced neuroinflammation, oxidative stress, and memory impairments.
Nutrients. 2019 Mar 17;11(3):648.
C57BL/6 mice
Acrolein-induced lung injury model
Intraperitoneal injection
60 mg/kg
Single dose, lasting 12 hours
To investigate the protective effects of hesperetin on acrolein-induced lung damage. Results showed that hesperetin pretreatment significantly improved lung tissue structure, reduced fibrosis and apoptosis marker protein expression, and decreased oxidative stress markers (e.g., Prx-SO3, HNE, and 8-OH-dG).
Redox Rep. 2018 Dec;23(1):188-193.
Sprague Dawley rats
High-fat diet and streptozotocin (STZ)-induced type 2 diabetes rat model
Oral gavage
Hesperetin 50 mg/kg/day, Metformin 100 mg/kg/day
Once daily for six weeks
To investigate the effect of hesperetin-enhanced metformin on alleviating cognitive impairment in diabetic rats and its mechanism
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