Naringin (NG) known as 4′,5,7-Trihydroxyflavanone 7-Rhamnoglucoside is a compound that falls under the classification of dihydroflavonoids. This complex compound comprises 4′,5,7-hydroxyflavone (saccharide ligand) conjoined with rhamnose-β-1,2-glucose ^[1]. The primary source of naringin (NG) is citrus fruit, although the concentration is significantly different across different species. For instance, Citrus aurantium subsp. (C.) reticulata boasts an NG content of 3383.6 μg/mL, while C. bergamia, on the other hand, contains a significantly lower quantity at 22.3 μg/mL. Notably, in C. paradisi, NG significantly surpasses other common citrus flavonoids, making it the dominant compound ^[2]. Meanwhile, NG is mainly found in the waste of fruit and vegetable products such as citrus peel. Yu Matsuo et al. obtained NG from C. natsudaidai peel waste extract with a yield of 23.8–27.0 mg/g dried material, which had a better odor than commercial citrus-flavor drinks ^[3]. Research on the biological activities of NG and the improvement of bioavailability is conducive to the comprehensive utilization of product waste and increases the added value of related products.

2. Anti-Inflammatory

NG exhibits potent anti-inflammatory properties, efficaciously mitigating acute inflammation instigated by pro-inflammatory factors. Overproduction of inflammatory mediators such as free radicals, cytokines, and chemokines, along with an escalated infiltration of inflammatory and immune cells, disrupt cellular and tissue functions and are associated with several acute and chronic diseases [21]^[4]. Specifically in macrophages, NG has been found to significantly suppress the production of inflammatory factors such as nitric oxide (NO), nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6). Moreover, NG also inhibits the activation of nuclear factor kappa-B (NF-κB) induced by lipopolysaccharide (LPS) in cells [22]^[5]. NF-κB serves as a pivotal mediator in cellular responses to external stimuli, often acting as an initial responder that potentially intensifies the expression of inflammatory factors [23]^[6]. In this context, NG’s role in inhibiting the activation of NF-κB has emerged as particularly significant, given its anti-inflammatory potential. Meanwhile, a study by Liu et al. demonstrated that NG alleviates the secretion of lung-tissue myeloperoxidase (MPO), iNOS activity, and TNF-α expression in a dose-dependent manner in LPS-induced inflammation mice. Concurrently, the degradation of the inhibitor of nuclear factor kappa-B-alpha (IĸB-α) and the translocation of protein NF-κB p65 are hindered, effectively inactivating NF-κB activation. These findings suggest that NG might exert substantial anti-inflammatory effects in lungs exposed to LPS, likely by inhibiting NF-κB activation [24]^[7]. Therefore, NG has been demonstrated to have significant potential as an effective anti-inflammatory agent.

3. Anti-Diabetes

Insulin resistance is a fundamental pathological feature of type 2 diabetes, often exacerbated by the impairment of insulin signaling. This impairment significantly aggravates diabetes symptoms by reducing insulin efficacy [25]^[8]. Research has demonstrated that NG ameliorates insulin resistance induced by a high-fat diet through the activation of the insulin pathway (phosphatidyl inositol 3 kinase (PI3K)/protein kinase B (PKB or AKT) and glucose transporters 4 (GLUT4) translocation. This activation induces GLUT4′s translocation to the plasma membrane), therefore facilitating a decrease in blood glucose levels [26]^[9]. In addition, NG enhances glucose uptake by promoting the translocation of GLUT2 in HepG2 cells under high glucose conditions. At the same time, it suppresses hepatic gluconeogenesis and promotes glycogen synthesis by activating the adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) pathway. As a result, blood glucose is absorbed by the peripheral organs, effectively reducing blood glucose levels [27]^[10]. Therefore, NG could be used as a potential candidate for treating type 2 diabetes. Moreover, NG has demonstrated potential for ameliorating diabetic nephropathy (DN), a typical complication of type 1 and type 2 diabetes. Zhang et al. found that NG suppressed the expression of NADPH oxidase 4 (NOX4) at both mRNA and protein levels through in vivo and in vitro model experiments of DN. The down-regulation of NOX4 notably reduces the expression level of Cleaved caspase3 in podocytes, resulting in significant suppression of apoptosis and reactive oxygen species levels. Meanwhile, it curtails the excessive accumulation of extracellular matrix (ECM) in mesangial and renal tubular cells, alleviating streptozotocin-induced oxidative stress injury and mitigating apoptosis and highly reactive oxygen species levels triggered by high glucose levels [28]^[11]. Therefore, NG has been demonstrated to have a therapeutic effect on DN complications, primarily through the mitigation of histiocytic symptoms associated with DN.

4. Hepatoprotective Activity

NG has been identified as a potential therapeutic agent in ameliorating symptoms of hepatic disease. Research conducted by Rossana Bugianesi et al. illustrated that NG is predominantly metabolized in the liver, and after oral ingestion of tomato paste rich in NG glycosides, it circulated in the body as a conjugated form [29]^[12]. This implied that NG sourced from plant-based foods is effectively absorbed by the body, enhancing its bioavailability. As a result, it can significantly contribute to preventing and treating liver disease in humans. Research has shown that NG (25 mg/L) effectively reduces alcohol-induced lipid accumulation in the subcutaneous layers and liver of the zebrafish model. Meanwhile, hepatocyte steatosis was inhibited, and liver damage caused by fat deposition was improved [28]^[11]. In further research, fat deposition was improved by decreasing the formation and accumulation of reactive oxygen species (ROS) in the liver [30]^[13]. Meanwhile, NG has the potential to regulate oxidative pressure and inhibit hepatocyte injury. In the experiment, NG treatment at 5 mg/L for 48 h significantly reduced the alcohol-induced lipid droplet accumulation in the livers of exposed larvae with a dose-dependent tendency. More specifically, NG significantly reduced the oxidative stress gene expression of cyp2y3 and fabp10α, which was induced by alcohol. Both oxidative stress genes were involved in the regulation of fatty acid metabolism and lipid uptake and transport. Furthermore, in zebrafish, the closest cyp2e1 homolog was cyp2y3, which is 43% identical to the human protein. NG also reduced hepatocyte apoptosis of zebrafish larvae in experiments of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, and played a positive role in anti-apoptosis. Moreover, NG exhibits the physiological activity of anti-apoptosis. Some related factors that cause lipid metabolism disorder, endoplasmic reticulum stress, and DNA damage were downgraded due to the intake of NG, and the phenomenon of apoptosis was reduced [31]^[14]. In addition, NG has been demonstrated to have significant efficacy in mitigating nonalcoholic fatty liver disease (NAFLD). First, NG reduced hepatic steatosis in rats subjected to a high-fat diet. This hepatoprotective activity appeared to be partially mediated by the activation of the AMPK pathway. Upon the activation of the AMPK pathway, there was a consequent re-establishment of reduced antioxidant enzyme activities, comprising superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione S-transferase (GST), as well as prevented inflammation [32]^[15]. The increase in antioxidant enzyme activities enhances liver detoxification and protects the liver from free-radical damage [33]^[16]. Meanwhile, NG has been shown to have significant potential in ameliorating the symptoms of cadmium-induced hepatotoxicity (at a concentration of 50 mg/kg NG) and nickel-induced hepatotoxicity (at 80 mg/kg NG) (Table 1). These were demonstrated by a notable decrease in lipid peroxidation and a substantial increase in the activity of antioxidant enzymes in rats [34]^[17]. Moreover, naringenin (50 mg/kg, an aglycone of NG) was shown to have a remarkably restorative effect on liver function abnormalities induced by dimethylnitrosamine (DMN) in mice [35]^[18]. In summary, the demonstrated hepatoprotective activities of NG substantiate its potential as a promising therapeutic candidate for liver diseases, highlighting its value for further clinical research.

5. Neuroprotective Activity

NG has been demonstrated to have tremendous potential for the prevention and therapeutic intervention of neurodegenerative diseases such as Parkinson’s disease, epilepsy, Huntington’s disease, and Alzheimer’s disease (AD) (Table 1). Investigations have revealed that NG has a protective effect on viable neurons affected by 3-nitropropionic (3-NP), a succinate dehydrogenase inhibitor known to induce neuronal injury and death in rats. This protective effect has been demonstrated by the reduction of radical species such as hydroxyl radical (29.36%), hydroperoxide radical (36.32%), and nitrite radical (45.62%) in 3-NP-treated rats. Moreover, NG ameliorated the tissue damage caused by 3-NP exposure by enhancing the GSH/GSSG ratio value by 74.17%. Additionally, NG significantly increased mRNA expressions of HO-1, NQO-1, GST-P1, and c-GCL by 60.78%, 72.5%, 64.71%, and 55.79%, respectively, in the treated rats compared with the 3-NP-induced group. Impressively, these expressions exceeded 75% compared to the control group of rats [36]^[19]. These increases were significant since HO-1, NQO-1, GST-P1, and c-GCL were induced by the nuclear erythroid 2-related factor 2 (Nrf2) [37,38]^[20][21]. Consequently, the pronounced neuroprotective effect of NG can be attributed to its potent antioxidant activity, mediated through the Nrf2 signaling cascade. NG has been seen to protect neurons by stimulating the production of neurotrophic factors and activating the Nrf2 signal transduction pathway [39]^[22]. In the case of AD patients, there is typically an overactivation of pro-inflammatory M1-type cells in the brain tissue, leading to excessive secretion of pro-inflammatory factors and cytotoxic substances [40]^[23]. NG has been shown to mitigate cognitive impairment in AD patients by regulating the balance of pro-inflammatory cells (M1 type) and anti-inflammatory cells (M2 type). Furthermore, NG improves abnormal behavioral features by enhancing the phagocytosis and clearance of Aβ-oligomer, therefore offsetting neurotoxicity and neuroinflammation [41]^[24]. This finding has established a theoretical framework for treating AD and presents a novel therapeutic approach. In short, NG offers promise as a prospective medication for treating and preventing neurodegenerative disorders.

6. The Drug Absorption Enhancer

NG and its derivatives play roles as solubilizers, boosting the absorption of other drugs, and elevating their bioavailability, as demonstrated in drugs such as paclitaxel, diltiazem, candesartan, and pranlukast. Paclitaxel, an anticancer drug, is characterized by poor solubility and challenging absorption into the body, predominantly due to the exocytosis of p-glycoprotein (p-gp) at the top of the intestinal epithelial cells [42]^[25]. Owing to these complexities, paclitaxel is mainly administered through intravenous injection, which, unfortunately, is prone to induce allergic reactions, therefore limiting its clinical application. However, studies have reported an elevated plasma concentration of paclitaxel when co-administered with NG’s prodrug 7-mPEG 5000-succinyloxymethyloxycarbonyl-paclitaxel, compared to when paclitaxel was administered alone [18]^[26]. This phenomenon suggests that NG effectively improves the bioavailability of paclitaxel, presenting a promising avenue for the development of oral paclitaxel medicines. Similarly, NG also enhances the bioavailability of diltiazem, a calcium-channel antagonist. It has been shown that metabolic enzymes and p-glycoprotein impede the absorption of diltiazem [43]^[27]. However, upon administration of NG (5 or 15 mg/kg), both the area under the plasma concentration–time curve (AUC) and the peak concentration (C_max) have been observed to double, indicating significant changes in pharmacokinetics and a marked improvement in bioavailability. In addition, Surampalli et al. explored the effect of NG on the absorption of candesartan (an antihypertensive drug) within the intestinal tract of rats using a single-channel perfusion model (Table 1). Their results illustrated that the lyophilized solid dispersion of NG significantly increases the maximum concentration (C_max) of candesartan and shortens the time (t_max) to reach C_max compared to when the drug was administered alone. This outcome was attributed to low concentrations of NG substantially inhibiting the function of p-glycoprotein [44]^[28]. Moreover, α-glycosylated NG significantly increased the apparent solubility of pranlukast hemihydrate (PLH, a drug used to treat bronchial asthma) in distilled water at 37 °C, as per the dissolution test. The apparent solubility of PLH increased from 0.17 ± 0.01 μg/mL in the control group to 14.54 ± 1.32 μg/mL, and this increase was proportional to the concentration of α-glycosylated NG [20]^[29]. Concurrently, the AUC of the physical mixture of PLH with α-glycosylated NG was 2.2 times greater than that of the PLH treatment alone in a rat model, indicating that α-glycosylated NG improved the oral absorption of PLH [20]^[29]. In summary, NG has emerged as a potential active ingredient capable of improving the bioavailability of drugs with poor solubility, reinforcing its pivotal role in drug absorption enhancement. These characteristics of NG, which greatly limit its application in practical production, mainly include low solubility, low permeability, short half-life, high plasma concentration fluctuation, bitter taste, and toxicity at high concentrations (≥200 μg/mL) [11]^[30]. Therefore, the solubilization of NG and the improvement of its bioavailability have become research hotspots. The solubilization methods of NG are summarized in the following table, including structural modification, solid dispersion, liposomes, preparation of nanoparticles, and amphiphilic molecular encapsulation, to provide a reference for solving NG’s poor-solubility problem.