IngredientsNeohesperidin (hesperetin 7-O-neohesperidoside) is a well-known flavanone glycoside widely found in citrus fruits. Structurally, neohesperidin (NHP) carries the systematic descriptor 3′,5,7-trihydroxy-4′-methoxy flavanone and is classified as a citrus flavonoid with inherent potent pharmacological properties. Neohesperidin is the 7-O-neohesperidoside of hesperetin, meaning that the aglycone hesperetin is glycosylated at the 7-position with the disaccharide neohesperidose. In comparison to hesperidin, which shares the same hesperetin aglycone but is conjugated with rutinose (α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside) at the 7-position, neohesperidin differs in the disaccharide configuration, featuring the α-1,2 linkage in neohesperidose rather than the β-1,6 linkage in rutinose. Neohesperidin exhibits defined stereochemistry across 11 chiral centers, including the (2S) configuration at the flavanone C-2 position, which contributes to its optical activity and biological specificity.
Neohesperidin, hesperidin, and hesperetin are citrus flavonoids from the flavanones subclass that have anti-inflammatory and antioxidant potential. Some flavanones are known to give the characteristic bitter taste of citrus, including naringin, neohesperidin, neoeriocitrin, and poncirin.
Neohesperidin is a flavanone naturally occurring in bitter oranges (Citrus aurantium) and is isolated by alcohol extraction. Citrus plants belonging to the Rutaceae family are one of the richest sources of flavonoids, including nobiletin, tangeretin, hesperidin, neohesperidin, rutin, narirutin, naringenin, and quercetin, which are well known for their beneficial pharmacological activities.
Flavanones constitute the majority of flavonoids in citrus fruits such as sweet (Citrus sinensis) and sour oranges (C. aurantium) and their near relatives — tangerines/mandarins (C. reticulata), tangors, and tangelos. Relevant chemical analytic literature has examined citrus flavanones including hesperidin, naringin, narirutin, eriocitrin, neohesperidin, didymin, neoeriocitrin, and poncirin. Sour oranges had a distinct flavanone profile dominated by naringin and neohesperidin and were highest in total flavanones (summed means of 48 mg/100 g aglycones).
Neohesperidin has also been found in bergamot (Citrus bergamia) juice, where its content was measured at 123.9 ± 1.7 mg/L among major flavanones, alongside naringin and neoeriocitrin. Huyou peel (C. paradisi cv. Changshanhuyou) has been found to be the best naringin and neohesperidin source, with neohesperidin at 2.76%; C. aurantium, a major ingredient of several citrus-related TCM preparations, is also a suitable source of naringin and neohesperidin.
Neohesperidin is commercially obtained in several forms. Neohesperidin is isolated from bitter oranges by alcohol extraction. The compound exists primarily as a standardized extract or purified powder for use in food, nutraceutical, and research settings. Neohesperidin is a natural flavonoid glycoside compound with considerable physiological and pharmacological activities; however, its bioavailability is limited due to poor solubility.
A closely related and industrially important derivative is neohesperidin dihydrochalcone (NHDC). Neohesperidin dihydrochalcone is a semi-synthetic flavonoid glycoside produced from neohesperidin present in the peel of bitter orange (Citrus aurantium L.; Rutaceae), through catalytic hydrogenation under alkaline conditions. Neohesperidin dihydrochalcone (NHD) is a chalcone derivative of NHP used as an artificial sweetener which also showed various pharmacological properties, especially antioxidant activity. The sweetening power of NHDC is approximately 1,500 times greater than that of sucrose, and its caloric value does not exceed 0.002 kcal/g.
In addition to the wide applicability of neohesperidin in the food industry, this flavanone can also be used as a non-nutritive agent in several other applications. In the pharmaceutical industry, neohesperidin can be used in cosmetic and dental products, such as toothpastes and oral care products.
Flavonoid-enriched tissues of citrus such as peel, immature fruit, and flower have been consumed as culinary seasonings and tea ingredients in China for centuries. Neohesperidin is among the principal flavonoids found in several important TCM source plants. Citrus × aurantium L., known in Chinese as Fructus Aurantii (FA), has been largely used as a Qi-invigorating herb in China for centuries.
Chenpi (also written chen pi or chimpi) is sun-dried mandarin orange peel used as a traditional seasoning in Chinese cooking and traditional medicine; it is aged by storing the peels dry. The taste is first slightly sweet, but the aftertaste is pungent and bitter. According to Chinese herbology, its attribute is warm. Chenpi contains volatile oils which include neohesperidin among its phytochemical constituents. Traditional Chinese herbal medicine uses the alcohol extracts of several citrus peels, including those extracted from mandarin orange and bitter orange.
The peel and fruit of Citrus varieties have been a raw material for some traditional Chinese medicine (TCM). Pure total flavonoids from Citrus maxima (Burm.) Merr., including naringin, hesperidin, narirutin, and neohesperidin, have attracted increasing attention for their multiple clinical efficacies. Based on existing in vitro and in vivo research, systematic reviews have examined the biological functions of these flavonoids and their components in preventing or treating liver metabolic diseases, cardiovascular diseases, intestinal barrier dysfunction, and malignancies.
In TCM recipes, citrus flavonoid-enriched ingredients usually contribute as "helpers," protecting main active components, enhancing absorption of main drugs, and exerting synergistic effects in the overall prescription. The traditional preparations were predominantly decoctions and dried peel powders from ripe or immature fruits, consumed either as hot teas, tinctures, or incorporated into multi-herb formulas targeting digestive, respiratory, and circulatory ailments.
Neohesperidin is a product of the phenylpropanoid pathway in citrus plants. The biosynthetic pathways, physicochemical properties, and ADME (absorption, distribution, metabolism, and excretion) of NHP have been characterized. Hydrolysis, glucuronidation, sulfation, glutamylation, N-butyryl glycylation, and lactylation are the major reactions involved in the metabolism of NHP.
The B-ring is considered the main active site of flavonoids for antioxidant activities and radical scavenging; the greater the substitutions made in adjacent positions, the stronger the antioxidant activity. Substituents such as methoxy groups increase lipophilicity of the molecule, as well as its membrane permeability and its interaction with cholesterol, improving cardiovascular protection.
Phase I metabolic reactions of hydrolysis and phase II reactions of glucuronidation, sulfation, glutamylation, N-butyryl glycylation, and lactylation are the main metabolic reactions of NHDC in vivo. A total of 19 metabolites — distributed in plasma, urine, feces, heart, liver, lung, kidneys, and brain — were screened in one metabolite profiling study, with 18 of them characterized for the first time.
Like the natural form of neohesperidin, NHDC is largely metabolized by the intestinal microflora and may have a beneficial therapeutic effect. Bioavailability of neohesperidin as an intact glycoside is limited; colonic bacteria cleave the glycosidic bonds to release the aglycone hesperetin, which is subsequently absorbed and conjugated. Bioavailability is limited due to poor solubility, and researchers have attempted to improve the solubility and bioavailability of NH by structurally modifying it using an immobilized lipase to improve lipophilicity.
Neohesperidin, a dihydroflavone abundantly detected in citrus flavonoids, has been demonstrated to have ROS-scavenging activity. The antioxidant mechanism involves scavenging of reactive oxygen species (ROS) and upregulation of endogenous antioxidant enzyme systems. Treatment with NHDC effectively alleviates LPS-induced endothelial permeability and organ damage by reducing reactive oxygen species production and enhancing the antioxidant response.
Neohesperidin suppresses the levels of serum inflammatory cytokines, myocardial damage markers, and oxidative stress markers, and increases the levels of antioxidants in myocardial ischemia/reperfusion rats. It also inhibits cell apoptosis and inhibits the phosphorylation of c-Jun N-terminal kinases (JNK) and nuclear factor kappa B (NF-κB) p65. NHDC exerts protective effects by inhibiting the release of IL-1β, IL-6, and TNF-α, and by decreasing the phosphorylation of key inflammatory signaling molecules, including transforming growth factor-β-activated kinase 1 (TAK1), extracellular signal-regulated kinases 1/2 (ERK1/2), and nuclear factor kappa B (NF-κB).
The likely mechanisms by which neohesperidin's anti-bone-loss and anti-inflammatory effects occur are due to both the inhibition of the NF-κB signaling pathway and the synthesis of inflammatory cytokines, such as IL-6 and IL-1β. In allergy models, NHDC and NH reduce OVA-induced food allergy related symptoms, and the underlying mechanism is closely related to the NOTCH/NF-κB pathway, which is associated with Th2 cell differentiation.
Neohesperidin shows a potent hypolipidemic effect in HepG2 cells loaded with free fatty acids and reverses pathological changes of lipid in acute or chronic dyslipidemia mouse models. Neohesperidin regulates lipid metabolism in vivo and in vitro via fibroblast growth factor 21 (FGF21) and AMP-activated protein kinase/Sirtuin type 1/peroxisome proliferator-activated receptor gamma coactivator 1α (AMPK/SIRT1/PGC-1α) signaling axis.
The anticancer mechanism of neohesperidin is regulated by a mitochondria-mediated (Bax and Bcl-2) caspase-dependent apoptotic and ROS-mediated pathway, which increases SMAC expression by 21.2% along with lowering the XIAP level by 36.5%. Network pharmacology analyses revealed that metabolite targets of NHDC were involved in pathways in cancer, ovarian steroidogenesis, proteoglycans in cancer, the PI3K-Akt signaling pathway, and progesterone-mediated oocyte maturation, indicating that these functional changes might result in potential novel functions or other side effects, such as a disorder of steroid hormones.
Previous studies have revealed that neohesperidin exhibits neuroprotective effects against middle cerebral artery occlusion (MCAO)-induced transient focal ischemia in the rat model by activating the Akt/Nrf2/HO-1 pathway.
Evidence level: Predominantly preclinical (cell and animal studies). No robust human clinical trials specific to neohesperidin inflammation endpoints have been published.
Neohesperidin has demonstrated a broad range of therapeutic and biological activities in the treatment of a variety of complex disorders, including neurodegenerative, hepato-cardiac, cancer, diabetes, obesity, infectious, allergic, and inflammatory diseases. In a 2024 cell study, NHDC effectively alleviated LPS-induced endothelial permeability and organ damage by reducing reactive oxygen species production and enhancing the antioxidant response. The mechanism involved inhibiting the release of IL-1β, IL-6, and TNF-α, and decreasing phosphorylation of TAK1, ERK1/2, and NF-κB. This suggests NHDC may provide protection against LPS-induced vascular dysfunction by reducing oxidative stress and activation of inflammatory signaling pathways.
In a murine model of sepsis-associated lung injury (SALI), key targets associated with SALI, including MAPK8, MAPK14, KDR, CASP3, and RHOA — which are strongly linked to the MAPK signaling pathway — were found to be influenced by NHDC. In vivo tests revealed that NHDC significantly reduces oxidative stress and inflammatory responses. In vivo, NHDC reversed oxidative stress markers (catalase, superoxide dismutase, glutathione, malondialdehyde, and reactive oxygen species), decreased TNF-α and IL-6 levels, and alleviated lung pathological injury.
Evidence level: Preclinical animal studies only. No published human clinical trials on neohesperidin for cardiovascular outcomes have been verified.
Neohesperidin exerts antiviral, antioxidant, anti-inflammation, and antitumor effects. In a study investigating the effect and mechanism of NEO on myocardial ischemia-reperfusion (I/R) injury, results indicated that NEO suppressed the levels of serum inflammatory cytokines, myocardial damage markers, and oxidative stress markers, and increased the levels of antioxidants in myocardial I/R rats. Furthermore, NEO inhibited the phosphorylation of JNK and NF-κB p65, suggesting a dual anti-apoptotic and anti-inflammatory mechanism in the myocardium. This was an experimental rat model study; its findings have not been replicated in human clinical trials.
Evidence level: Animal models (moderate-quality preclinical evidence). No human clinical trials specifically on neohesperidin for glycemic control have been verified.
In a 6-week study using KK-A(y) diabetic mice, KK-A(y) mice were used as the diabetic experimental model. Treatment with NHP significantly decreased fasting glucose, serum glucose, and glycosylated serum protein (GSP). It significantly elevated oral glucose tolerance and insulin sensitivity and decreased insulin resistance in the diabetic mice. In addition, NHP significantly decreased serum triglycerides (TG), total cholesterol (TCH), leptin level, and liver index in the KK-A(y) mice.
In a high-fat diet mouse model, mice were fed either a chow diet or HFD with or without oral gavage of NHP for 12 weeks. NHP was found to increase mitochondrial biogenesis, improve hepatic steatosis, and reduce systematic insulin resistance in high fat diet (HFD) fed mice. NHP treatment obviously improved the levels of fasting blood glucose (FBG), fasting serum insulin (FINS), and HOMA-IR in HFD-fed mice. Results from oral glucose-tolerance tests (OGTT) and insulin-tolerance tests (ITT) showed that NHP also markedly improved peripheral insulin resistance and glucose intolerance in HFD mice.
The molecular mechanism demonstrated that NHP elevates hepatic mitochondrial biogenesis and fatty acid oxidation by increasing PGC-1α expression, mediated through activation of the AMPK pathway.
Important limitation note: The related compound hesperidin, which shares the same aglycone core, has been subjected to systematic review in humans. A meta-analysis showed that hesperidin supplementation did not significantly affect serum levels of fasting glucose, insulin, HbA1c, HOMA-IR, or QUICKI levels, and the overall effects were stable in sensitivity analysis. Whether these findings extend to neohesperidin in humans remains unknown, as no clinical trials have been conducted.
Evidence level: Animal and cell-based studies only. No human clinical data verified.
Studies suggest that neohesperidin dihydrochalcone (HDN) may protect against liver ischemia/reperfusion (I/R) injury through activating the Akt pathway by ameliorating liver oxidative stress, suppressing inflammation, and preventing hepatocyte apoptosis. Treatment with the Akt inhibitor LY294002 in wild-type mice blocked the hepatoprotective effects, confirming the mechanism. HDN may be a useful factor for liver injury protection and a potential therapeutic treatment for liver I/R injury.
Extensive work has been done in assessing the anti-inflammatory, hepatoprotective, and neuroprotective activities of neohesperidin and neohesperidin dihydrochalcone in various in vitro models of diseases. However, human clinical data for these hepatoprotective effects are absent from the published literature.
Evidence level: In vitro and animal studies. No human clinical trials identified.
Neohesperidin is abundant in citrus flavonoids and possesses reactive oxygen species scavenging activity and neuroprotective effects in vitro. In a study using a rat model of middle cerebral artery occlusion (MCAO) to investigate neuroprotective effects, NH significantly improved neurological functions and attenuated MCAO-induced infarct volume, pathological changes, and neuronal loss. The operative mechanism was identified as activation of the Akt/Nrf2/HO-1 pathway.
Neohesperidin has also shown neuroprotective effects against H₂O₂-caused and Aβ-induced cytotoxicity in vitro. Studies have additionally investigated inhibition of β-amyloid aggregation by neohesperidin and its neuroprotective effect on primary hippocampal cells against β-amyloid-induced toxicity. These findings are restricted to preclinical models.
Evidence level: In vitro and animal studies exclusively. No clinical evidence in humans.
Neohesperidin, a key natural flavonoid glycoside compound derived from bitter orange (Citrus aurantium), has been found to have potent physiological and pharmacological activities, including a strong anti-inflammatory and neuroprotective activity, the ability to inhibit differentiation of adult osteocytes, and an anti-proliferative effect on human liver cancer cells.
In a study of osteosarcoma cell lines, neohesperidin has anti-oxidative and anti-inflammatory properties and exerts extensive therapeutic effects on various cancers. Osteosarcoma cell lines were exposed to different concentrations of neohesperidin, and neohesperidin could inhibit proliferation and induce apoptosis in SJSA and HOS cells via ROS/JNK signaling pathway activation.
In a study of lung cancer cell lines (A549 and LLC-1), the mechanism involved mitochondria-mediated (Bax and Bcl-2) caspases-dependent apoptotic and ROS-mediated pathway.
In an in vivo colorectal tumorigenesis model, NHP inhibited colorectal tumorigenesis in the APC min/+ transgenic mouse model, as well as induced apoptosis and blocked angiogenesis in vivo. The in-cell study suggested that this tumorigenic preventative effect of NHP is not due to the direct impact on tumor cells. Using 16S rRNA gene-based microbiota sequencing, the relative abundance of Bacteroidetes was decreased, while Firmicutes and Proteobacteria were increased in the presence of NHP. These findings indicate a possible indirect, microbiota-mediated anti-tumor mechanism, though this remains preliminary and has not been studied in humans.
Evidence level: In vitro and animal models. No human clinical trial data on neohesperidin specifically.
Neohesperidin, hesperidin, and hesperetin are citrus flavonoids from the flavanones subclass that have anti-inflammatory and antioxidant potential. Neohesperidin, in the form of neohesperidin dihydrochalcone (NHDC), also has dietary properties as a sweetener. In general, these flavanones have been investigated as a strategy to control bone diseases, such as osteoporosis and osteoarthritis.
In vitro studies showed that these flavanones exerted antiosteoclastic and anti-inflammatory effects, inhibiting the expression of osteoclastic markers and reducing the levels of reactive oxygen species. In bone, flavonoids exert an anticatabolic effect, reducing the resorption process and favoring bone formation. In dental tissue, flavonoids have anticollagenolytic activity on the dentin matrix, inhibiting the proteolytic activity of MMPs and acting as natural collagen stabilizers. In addition, flavonoids may exert an antimicrobial effect, inhibiting the proliferation of oral bacterial strains.
Evidence level: Animal studies only. Preliminary and mechanistic.
Neohesperidin (NHP), a naturally occurring flavanone glycoside in citrus fruits, has anti-inflammatory properties. The efficacy and mechanism of NHP in countering prolonged high-fat diet-induced inflammation were studied in rats given intragastric administration of NHP for 12 consecutive weeks. NHP was found to be effective in reducing colorectal inflammation at doses of 40–80 mg/kg body weight by intragastric administration, with significant decreases in inflammation markers such as TNF-α and IL-1β levels. It also improved intestinal mucosal tissue integrity and reduced HFD-stimulated colorectal inflammation via the JAK2/STAT3 pathway. Furthermore, intestinal microbiota sequencing results showed that NHP intervention significantly downregulated the Firmicutes/Bacteroidetes ratio.
Administration of NHP resulted in a significant increase in Bacteroidetes and a reduction in Firmicutes proportions in a dose-dependent manner. Lactobacillus, which produces lactic acid and plays a crucial role in maintaining the intestinal mucosal barrier, regulating the immune system, and promoting digestion and absorption, exhibited a significant increase in abundance in the NHP 80 mg/kg group.
No standardized human dosage for neohesperidin as a therapeutic supplement has been established through clinical trials. The dosages below are those reported in preclinical research only and are presented solely for scientific reference, not as recommendations.
Further in vivo and in vitro studies on mechanistic potential are required before clinical trials to confirm the safety, bioavailability, and toxicity profiles of neohesperidin.
Neohesperidin dihydrochalcone is not only highly sweet but also has flavor-enhancing properties, and accordingly has a wide range of uses in foods and beverages in the countries of the European Union, where it is an authorized sweetener. The precursor neohesperidin itself has GRAS status in the United States as a natural extractive from citrus.
The European Food Safety Authority conducted a formal re-evaluation of neohesperidine dihydrochalcone (E 959) in 2022. The toxicity data set consisted of studies on subchronic and prenatal developmental toxicity in rodents. No human studies were available, neither retrieved in the literature nor submitted by the interested business operators. The panel considered the available data sufficient to establish a new ADI. Overall, no adverse effects on health were identified for neohesperidine dihydrochalcone based on the three toxicological studies considered. Based on the weight of evidence analysis, the panel considered it unlikely that neohesperidine dihydrochalcone would lead to adverse effects on health in animals in the dose ranges tested. The panel also considered that the lack of human data does not affect the overall confidence in the body of evidence and that a carcinogenicity study was considered not warranted.
The EFSA panel derived an ADI of 20 mg/kg bodyweight per day based on a NOAEL of 4,000 mg/kg bw per day from a 13-week study in rat, applying the standard default factors of 100 for inter- and intraspecies differences and of 2 for extrapolation from subchronic to chronic exposure.
Chronic toxicity assessments, including 90-day subchronic studies in rodents, establish a no observed adverse effect level (NOAEL) of 750 mg/kg body weight per day in males and 850 mg/kg body weight per day in females for NHDC. A 13-week study reported a higher NOAEL of approximately 4,000 mg/kg body weight per day.
In the 90-day study, the highest dose group showed decreased body weight gains in males throughout the study and in females in the first two weeks. Microscopic examination did not reveal any treatment-related changes in the caecum or in other organs or tissues. The panel noted that body weight changes in rats and mice in two of the three evaluated studies were within 10% of control values and were considered to be non-adverse.
Considering the potential benefit of NHDC for health, in vitro and animal model studies have been conducted to evaluate possible mutagenic potential. The EFSA assessment did not identify genotoxic or mutagenic signals in the studies reviewed, and a carcinogenicity study was considered not warranted. Prenatal developmental toxicity was assessed as part of the data package, and no findings raised concern at toxicologically relevant doses.
A notable pharmacokinetic interaction concern identified in metabolite profiling research is relevant: network pharmacology analyses revealed that metabolite targets of NHDC were involved in pathways including steroid hormone biosynthesis and progesterone-mediated oocyte maturation, indicating that these functional changes might result in potential novel functions or other side effects, such as a disorder of steroid hormones. This finding is based on network pharmacology modelling in rats and warrants further investigation; its clinical relevance in humans is not established.
Neohesperidin is a natural flavonoid glycoside compound with considerable physiological and pharmacological activities; however, its bioavailability is limited due to poor solubility. This constraint means that observed biological effects in preclinical models may not translate directly to equivalent effects in humans at comparable nominal doses. Interindividual differences in gut microbiota composition will further affect the extent of conversion of the glycoside to the bioactive aglycone.
Further in vivo and in vitro studies on mechanistic potential are required before clinical trials to confirm the safety, bioavailability, and toxicity profiles of neohesperidin. No human studies were available, neither retrieved in the literature nor submitted by the interested business operators at the time of the 2022 EFSA re-evaluation for the derivative NHDC. This applies a fortiori to neohesperidin itself in supplemental or therapeutic contexts.
Health conditions that Neohesperidin may help support.
Body systems that Neohesperidin may help support.
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