Exploring the Hepatoprotective Effects of Naringin: A Systematic Review and Meta-Analysis of Preclinical Evidence

Abstract

This study aimed to perform a systematic review and meta-analysis on the hepatoprotective effects of naringin based on the pre-clinical evidence.

A detailed literature search was performed using online databases such as Google Scholar, PubMed, Scopus, and EMBASE. Based on the predefined inclusion and exclusion criteria, 20 studies were considered for meta-analysis.

The outcomes of the meta-analysis revealed that naringin improved liver function by reducing the elevated levels of ALT, AST, GGT, LDH, ALP, and bilirubin. It improved the enzymatic and non-enzymatic antioxidants, such as SOD, catalase, GSH, GST, GR, and GPx (p < 0.05 for all the parameters), while reducing the LPO/MDA levels (p < 0.05). NAR treatment also alleviated the levels of inflammatory mediators (IL-1β, IL-6, and TNF-α, p < 0.001 for all the parameters; NF-κB, p = 0.29) in various animal models of liver injury. In addition, NAR significantly reduced the caspase-3 and Bax/Bcl-2 ratio (p < 0.05) compared to the control group. Furthermore, naringin treatment has normalised the liver and body weights compared to the disease control group.

This systematic review and meta-analysis demonstrate that naringin significantly improved the liver function in various animal models of liver injury, via potent antioxidant and anti-inflammatory mechanisms.

Keywords

naringin - hepatoprotection - antioxidant - anti-inflammatory - hepatotoxicity

Introduction

The liver is a multifunctional metabolic organ that is vital for proper metabolism. As the liverʼs diverse array of essential functions helps sustain homeostasis by maintaining a stable internal environment for all other organs within the body, the liver works to ensure stability as one of our most critical physiological regulators. The liver performs numerous pivotal roles in metabolic activities, detoxification, and production of bile and essential proteins [1], [2]. Liver diseases like NAFLD, hepatitis, liver fibrosis, and liver cirrhosis are major health concerns worldwide, affecting millions of people [1], [2], [3]. These disorders can lead to total liver failure, along with other severe complications. The liver plays a crucial role in metabolism, but it is highly susceptible to damage. Therefore, more research is needed to identify therapies that can protect the liver from a variety of harmful factors, such as medications, toxins, and conditions that could threaten its health.

The published literature suggests that naringin is one of the major phytoconstituents present in citrus fruits, and it is playing a pivotal role in various pharmacological properties of citrus fruits [4], [5]. Naringin is a member of the flavanone class of flavonoids, which is also known chemically as 4′,5,7-trihydroxyflavanone-7-rhamnoglucoside [5], [6], [7]. Numerous studies have been done on naringinʼs pharmacological properties, primarily in citrus fruits like oranges and grapefruits. Naringin has the potential to influence numerous cellular pathways that are important for liver injury and regeneration, making it a promising hepatoprotective molecule in terms of pharmacology [5], [8].

Investigations into naringinʼs hepatoprotective, anti-inflammatory, and antioxidant impacts through diminishing oxidative stress and inflammation in the liver have suggested its viability as a possible therapeutic alternative for liver health issues, given its proven means to safeguard hepatic cells from harm through its multitargeted properties [7]. Naringin has shown favourable results in experimental investigations regarding protecting the liver from various insults.

Despite the growing research on naringinʼs hepatoprotective properties and the fact that there is much literature on its benefits and hepatoprotective properties, no meta-analysis has been performed so far. There has been limited generalisability and inconsistent results due to study methods and outcome variability. The known studies have employed diverse experimental models, doses, treatment durations, and outcome measures, culminating in inconsistent and unsatisfactory results due to the variability in their methodological approaches. Conclusions on the effectiveness of naringin as a hepatoprotective drug are hampered by this heterogeneity.

SR and MA yielded a reliable method for combining data from numerous studies, improving statistical power, and yielding a more accurate evaluation of naringinʼs hepatoprotective effects. By synthesising information from multiple sources, one obtains a rigorous technique that permits systematic assessment and meta-analysis to surmount the constraints of singular examinations [9]. This methodology enables a quantitative examination of the aggregated outcomes, yielding more accurate approximations of the actual impact magnitude of naringin on hepatoprotection. It also allows us to investigate heterogeneous sources, evaluate publication bias, and produce evidence-based suggestions for clinical practice and future research avenues. By comprehensively surveying and quantitatively synthesising the wide body of pertinent research literature, this systematic review and meta-analysis was aimed at consolidating and evaluating the evidence from relevant investigations examining the possibility of the hepatoprotective effect of naringin.

Even with the encouraging results from preclinical research, more thorough human RCTs are demanded to determine the efficacy and safety of naringin in human liver diseases. Thorough human pharmacokinetic investigations are necessary to establish dosage ranges and resolve initial safety and tolerability concerns before moving on to larger-scale endpoint trials. Hence, this SR and MA may help scientists decide whether to investigate the hepatoprotective roles of naringin in a clinical setting.

Methodology

A detailed literature search was performed for articles published until December 2023 using the Medline/PubMed, Embase, Scopus, and Google Scholar databases. An extensive literature search was conducted using MeSH terms and keywords. A combination of “naringin”, “hepatoprotective”, “hepato-protective”, “hepatoprotection”, “liver”, “oxidative stress”, “stress”, “antioxidant”, and “hepatic disorders” is used as a combination of free text and thesaurus terms to search for suitable articles to consider in this study. During an initial search, no RCTs or other clinical papers were found that apply to the medicinal uses of naringin in liver conditions. Moreover, this study focuses only on the preclinical research confined to the therapeutic advantages of naringin in various hepatic disorders.

Study selection

All articles retrieved were filtered for duplicate studies using Microsoft Excel. Conference proceedings and commentaries have been excluded from the study. Every research article obtained from the databases underwent “abstract or full-length copy” screening initially, and the articles suiting the selection criteria were included for analysis, regardless of the experimental approach.

Data collection and extraction

Every study was thoroughly examined using the inclusion and exclusion criteria ([Table 1]). Title- and abstract-level screenings were done initially, followed by the assessment of full-text-level articles. The data collected from included studies were the author, year of publication, details on treatment groups, including drug name, dose, route of administration, number of animals in each group (n), and parameters mentioned in each study. Data extraction was performed by selecting those parameters with enough studies to perform a meta-analysis. The data for every parameter were extracted from each study for the control and treatment groups. The highest dose group data were chosen and extracted in cases of multiple doses used (low, medium, and high doses). The data from the bar graphs/line graphs were extracted using the web tool Plot Digitizer. The mean and standard deviation of the retrieved data were reported. Furthermore, 10% of the mean was used as the default value for standard deviation for each of the naringin and control groups in the absence of SD or SEM rather than zero.

Table 1 Inclusion and Exclusion Criteria.

Inclusion Criteria	Exclusion Criteria
Research articles published involving data for treatment, normal, and disease control groups.	Studies performed without control.
All research articles were published in the English language.	Articles published in languages other than English.
Studies with quantitative data on various parameters.	Any paper without quantitative data.
Full-length articles.	Only abstracts.
Naringin as a single entity was included.	Studies involving fruit extracts or a combination of other ingredients with naringin.
All studies dealing with liver disorders and hepatoprotection.	All other studies dealing with disorders other than liver/ hepatoprotection.
Articles published until December 2023.	All articles are beyond the scope.
	Studies with hapatic/liver cancer as a disease.
	Duplicates, book chapters, review articles.

Parameters

A meta-analysis was conducted on morphological parameters including body and liver weights. Serum hepatic markers including alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transferase, lactate dehydrogenase, and total bilirubin were analysed along with other serum biochemical parameters, like total protein, cholesterol, TG, low-density lipoprotein, high-density lipoprotein, and albumin. Oxidative stress markers such as reduced glutathione, superoxide dismutase, glutathione peroxidase, CAT, GST, glutathione reductase, thiobarbituric acid reactive substances, MDA/LPO, nitric oxide, and inducible nitric oxide synthase were included in the analysis. Inflammatory mediators included TNF-α, NF-KB, IL-1beta, and IL-6. Apoptosis markers included the caspase-3 and Bax/Bcl-2 ratio. These parameters were compared between the naringin-treated group and the disease-control group.

Risk of bias assessment

The credibility of the included articles was analysed using the SYRCLEʼs risk of bias assessment (RoB) tool. The Cochrane Handbookʼs recommendations were used to assess the RoB in the included articles. The tool assesses the studies based on 10 different parameters. We also assessed RoB using each domain of bias for every included study and marked it as either “yes”, “unclear”, or “no”. The “yes” judgment indicates that the risk of bias is low, and the “no” judgment indicates a high degree of bias risk. If the details of the report are insufficient to assess the appropriate risk of bias, the judgment will be “unclear” [4], [6].

Statistical analysis

The meta-analysis was performed using Review Manager (RevMan 5.4). Since every outcome indicator in the included studies was a continuous variable, a comprehensive effect analysis was conducted by inverse variance (IV) determined using the random effect model with 95% confidence intervals (95% CIs) with a standardised mean difference (SMD) as the effect measure. The I² statistic was used to calculate heterogeneity. This test calculates the proportion of research result variation related to heterogeneity as opposed to sampling error. A value of I² of less than 40% was deemed insignificant. Conversely, moderate to high heterogeneity was defined as an I² value greater than 40%. A sensitivity analysis was conducted to assess the reliability of the results [4], [6].

Results

Selection of literature

A total of 549 studies were retrieved through the MeSH terms search of records across various databases, of which 21 studies were retrieved from PubMed/Medline, 35 studies were retrieved from Scopus, 467 studies from Google Scholar, and 26 studies from Embase based on the pre-defined search criteria. The remaining 522 studies were further screened after removing duplicate studies. According to the eligibility criteria, 28 studies, after reviewing their titles and abstracts, were included in the study. Furthermore, three articles dealing with hepatic carcinoma, as well as four in vitro studies and one ex vivo study, with insufficient data for meta-analysis were removed. Eventually, 20 studies were considered for this meta-analysis. The PRISMA flow diagram is illustrated as [Fig. 1], and descriptions of included studies are given in [Table 2].

Fig. 1 PRISMA Flow Diagram.

Table 2 Description of included studies.

Sl.no	Study	Dose, Route, and Treatment Duration	Model Used	Parameter(s)
1	Khaled SS et al., 2023 [14]	10 mg/kg, naringin orally every other day for 6 weeks; (n1=6; n2= 6)	Taxol-induced hepato-toxicity in Wistar rats.	Total bilirubin, AST, ALT, ALP, MDA/LPO, LDH, GGT, serum albumin, liver caspase-3, GSH, GPx, SOD
2	Mahdavinia M et al., 2021 [24]	NAR= 40, 80, and 160 mg/kg 30 consecutive days along with BPA or alone, orally (n1=6; n2= 6)	Bisphenol A-induced hepatotoxicity in male rats.	Body weight, liver weight; biochemical assays: AST, ALT, LDH, and ALP, as well as LDL, HDL, TG, and cholesterol; assessment of oxidative stress: SOD, GPx, CAT, glutathione, and MDA levels
3	Pari L and Amudha K, 2011 [11]	Naringin was administered orally (20, 40, and 80 mg/kg body weight) for 20 days (n1=6; n2= 6)	Nickel-induced toxicity in male Wistar rats.	AST, ALT, ALP, and LDH. GGT; TBARS; ascorbic acid, α-tocopherol, GSH, SOD, CAT, GPx, GST, GR, G6PD, total protein content; total bilirubin, liver weight; body weight
4	Rodríguez V et al., 2018 [26]	NAR: 10,40,80 mg/kg, s. c.; rats treated daily for 30 days (n1=5,6,8) (n2=5,6,8)	Hepatotoxicity in streptozotocin-induced diabetic rats.	Serum biochemical analysis: serum glucose, TG, total cholesterol, ALT, AST, ALP, GSH; CAT and SOD; NO levels; caspase-3, Bax, Bcl-2.
5	Marzook E.A et al., 2020 [13]	NAR: 80 mg/kg; orally 3 times weekly by intragastric intubation (n1=8; n2= 8)	Carbon-tetrachloride-induced liver damage in male albino rats.	Hepatic oxidative stress markers: GSH, SOD activity MDA; IL-6
6	Ali AL et al., 2017 [17]	NAR: 100 mg/kg; p.o: dissolved in water for 21 days (n1=6; n2= 6)	Lambda cyhalothrin (LTC)-induced hepatotoxicity in male Wistar rats.	Biochemical assays: SOD, catalase, GPX, GST, LPO level by measuring TBARS; AST, ALT, ALP, and LDH, LPO, GR, GST
7	Hemaid A.E et al., 2023 [18]	Naringin = 50, 100 mg/kg orally 28 days (n1=7; n2= 7)	Furan-induced hepatotoxicity in male albino rats.	Biochemical analysis: AST, ALT, and ALP, serum albumin and total protein total bilirubin, cholesterol, TG
8	Ali AL et al., 2015 [15]	100 mg/kg BW of naringin dissolved in water orally for 21 days (n1=6; n2= 6)	Pyrethroid-deltamethrin-induced hepatotoxicity in male Wistar rats.	Biochemical assays, SOD, CAT, GPx, GR, GST, and LPO were determined with TBARS; hepatic enzymes: AST, ALT, ALP, and LDH
9	Esuola et al., 2023 [10]	Naringin:100, 200 mg/kg through oral gavage for 2 weeks (n1=6; n2= 6)	Bisphenol A-induced hepatotoxicity in 31-day-old cockerel chicks.	Biochemical assays: H2O2 generation, LPO/MDA), GSH, SOD, GPx and GST; total protein, albumin, total bilirubin, AST, ALT, and ALP; caspase 3 and TNF-alpha
10	Ahmed O. M. et al., 2019 [16]	Naringin = 20 mg/kg oral gavage every other day for 4 weeks (n1=6; n2= 6)	N-Acetyl-p-aminophenol-induced liver injury in Wistar rats.	Liver function biomarkers such as “ALT, AST, ALP” GGT, LDH, albumin, total bilirubin, oxidative stress markers: LPO, GSH, GST SOD, GPx; TNF-alpha IL-4, Bax, caspase-3, and Bcl-2.
11	Lin Z et al., 2022 [20]	NAR oral gavage, 50, 100 mg/kg (n1=8; n2= 8)	Paracetamol-induced hepatotoxicity in mice.	Serum ALT/AST activity; GPx and MDA
12	Adil M et al., 2016 [21]	Naringin 20, 40, and 80 mg/kg oral gavage for 14 days (n1=6; n2= 6)	Paracetamol-induced hepatotoxicity in adult male Wistar rats.	Total protein, SOD, GSH, MDA, and NO; albumin, ALP, cholesterol, bilirubin, HDL, LDH, LDL, AST, ALT, TG, total bilirubin.
13	Anis A et al., 2022 [22]	80 mg/kg NAR dissolved in distilled water 3 times a week for 8 consecutive weeks (n1=7; n2= 7)	Di – n-butyl phthalate-induced hepatotoxic effects in male albino rats.	Serum ALT, AST, serum oxidant/antioxidant biomarkers assessment: MDA, TCA.
14	Hassan R.A et al., 2021 [19]	NAR: 20 mg/kg; po for 4 weeks (n1=6; n2= 6)	Diclofenac-induced hepatotoxicity in male Wistar rats.	ALT, AST, serum LDH, ALP, GGT, serum albumin, serum bilirubin, MDA/LPO, GSH, GPx, SOD, TNF-α, IL-17, and IL-4 levels.
15	Gelen V et al., 2017 [23]	NAR=100 mg/kg ip for 14 days (n1=10; n2= 10)	5-Fluorouracil-induced hepatotoxicity in male adult Sprague–Dawley rats.	Liver weight, SOD activity, GSH and TBARS levels; AST; ALT; ALP, IL-6, IL-1α, and TNF-α;
16	Akamo AJ et al., 2021 [12]	NAR 50 mg/kg, 100 mg/kg, 200 mg/kg. were administered orally to the animals with a gavage needle daily for fourteen consecutive days at 8.00 – 9.00 h (n1=5; n2= 5)	Cyclophosphamide-induced hepatotoxicity in female albino Wistar rats.	Total protein; ALT, AST, GGT, ALP, and LDH; MDA, NO; GST, GSH, GR, SOD, CAT, GPx; IFN-α1, IL-1β, IL-1, TGF-beta 1
17	Caglayan et al., 2018 [25]	NAR 50 mg/kg/day, 100 mg/kg/day orally for 7 days (n1=7; n2= 7)	Cyclophosphamide-induced hepatotoxicity in male Wistar rats.	ALP, AST, ALT; SOD, GPx, CAT, GSH, MDA, total protein content, NF-KB, TNF-alpha, IL-6, IL-1β; COX-2 and iNOS.
18	Xi Y et al., 2023a [27]	In-vivo NAR 30,60,120 mg/kg oral gavage once a day for 1 week.; (n1=6; n2= 6)	Doxorubicin-induced hepatotoxicity in BALB/c mice.	ALT and AST, and LPO(MDA), SOD, GSH, CAT; IL-1 beta, IL- 6, TNF-alpha
19	Badr HM et al., 2009 [28]	Naringin 300 mg/kg p. o. route daily for 6 weeks (n1=10; n2= 10)	Carbon-tetrachloride-induced hepatotoxicity in male Sprague–Dawley rats.	ALT, AST, ALP, and bilirubin.
20	El-Mihi KA et al., 2017 [29]	Naringin 40 mg/kg; po gavage for 6 weeks (n1=8; n2=8)	Thioacetamide-induced hepatotoxicity in adult male Sprague–Dawley rats.	ALT, AST, albumin, total protein, and total bilirubin; CAT, SOD and GPx, LPO/MDA, IL-6

Risk of bias assessment

The Risk of Bias Assessment for the included studies was conducted using SYRCLEʼs tool by Fayaz M and reviewed by co-authors. Ranking criteria: the “yes” judgment indicates that the risk of bias is low, and the “no” judgment indicates a high degree of bias risk. If the details of the report are insufficient to assess the appropriate risk of bias, the judgment will be “unclear”. This study does not benefit from participant or staff blinding or outcome assessment blinding, since this study only includes pre-clinical investigations. In contrast, the factors above are assessed for patient-involved studies and randomised clinical trials. Since most of the included studies have not stated the baseline for the parameters under evaluation, allocation concealment primarily displays an uncertain chance for bias, whereas research where the animals are randomly allocated to normal control, disease control, and treatment groups can be considered as low RoB. Random sequence generation is a domain of RoB assessment wherein random sequences are generated using various methods. Studies that mention the process of random sequence generation can be considered low risk and high RoB where the method of sequence generation is not mentioned. Since this study deals with the pre-clinical model, performance bias and detection bias do not apply. Incomplete outcome bias includes mortality of rats in between the experiment/study. Since none of the studies reported mortality of animals, it is of low risk. Selective reporting indicates excluding specific parameters that were clearly defined in the methodology of a particular study but have no data or are selectively excluded from results. Other bias includes any other possible bias that might be relevant to individual studies. The risk bias involved with the included studies is represented in [Table 3].

Table 3 Risk of Bias Assessment for Included Studies Using SYRCLEʼs Tool.

Author	1	2	3	4	5	6	7	8	9	10	Score
Ranking criteria: the “yes” judgment indicates that the risk of bias is low, and the “no” judgment indicates a high degree of bias risk. If the details of the report are insufficient to assess the appropriate risk of bias, the judgment will be “unclear”. Item 1 – Was the allocation sequence adequately generated and applied? Item 2 – Were the groups similar at baseline or were they adjusted for confounders in the analysis? Item 3 – Was the allocation adequately concealed? Item 4 – Were the animals randomly housed during the experiment? Item 5 – Were the caregivers and/or investigators blinded from knowledge about which intervention each animal received during the experiment? Item 6 – Were animals selected at random for outcome assessment? Item 7 – Was the outcome assessor blinded? Item 8 – Were incomplete outcome data adequately addressed? Item 9 – Are reports of the study free of selective outcome reporting? Item 10 – Was the study apparently free of other problems that could result in high risk of bias?
Khaled SS et al., 2023 [14]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	Yes	Unclear	5
Mahdavinia M et al., 2021 [24]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	Yes	Unclear	5
Pari L and Amudha K, 2011 [11]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	No	Unclear	4
Rodríguez V et al., 2018 [26]	Unclear	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	Yes	Unclear	3
Marzook E.A et al., 2020 [13]	Unclear	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	Yes	Unclear	3
Ali AL et al., 2017 [17]	Unclear	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	Yes	Unclear	3
Hemaid A.E et al., 2023 [18]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	Yes	Unclear	5
Ali AL et al., 2015 [15]	Unclear	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	Yes	Unclear	3
Esuola et al., 2023 [10]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	No	Unclear	4
Ahmed O. M. et al., 2019 [16]	Unclear	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	Yes	Unclear	3
Lin Z et al., 2022 [20]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	Yes	Unclear	5
Adil M et al., 2016 [21]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	No	Unclear	4
Anis A et al., 2022 [22]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	Yes	Unclear	5
Hassan R.A et al., 2021 [19]	Unclear	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	Yes	Unclear	3
Gelen V et al., 2017 [23]	Unclear	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	Yes	Unclear	3
Akamo AJ et al., 2021 [12]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	No	Unclear	4
Caglayan et al., 2018 [25]	Unclear	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	No	Unclear	2
Xi Y et al., 2023 [27]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	Yes	Unclear	5
Badr HM et al., 2009 [28]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	Yes	Unclear	5
El-Mihi KA et al., 2017 [29]	Unclear	Yes	Unclear	Yes	Unclear	Yes	Unclear	Yes	Yes	Unclear	5

Effect of naringin on biochemical parameters

Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transferase, lactate dehydrogenase, and total bilirubin are among the metrics commonly employed to evaluate the liverʼs functioning and condition. Usually, the levels of these markers will be elevated above the normal range during liver disease or toxicity. The results of this meta-analysis showed that consuming naringin significantly lowered ALT levels (IV: − 3.65 [− 4.62, − 2.68] at 95% CI, p < 0.00 001, I² = 79%) ([Fig. 2 A]), GGT (IV: − 3.59 [− 5.17, − 2.02] at 95% CI, p < 0.00 001, I² = 61%) ([Fig. 2 B]), LDH (IV: − 5.52 [− 7.45, − 3.59] at 95% CI, p < 0.00 001, I² = 81%) ([Fig. 2 C]), AST (IV: − 3.63 [− 4.57, − 2.69] at 95% CI, p < 0.00 001, I² = 77%) ([Fig. 2 D]), ALP (IV: − 3.36 [− 4.52, − 2.20] at 95% CI, p < 0.00 001, I² = 83%) ([Fig. 2 e]), total bilirubin (IV: − 2.10 [− 3.40, − 0.80] at 95% CI, p < 0.002, I² = 84%) ([Fig. 2 F]) in comparison with disease control. These results imply that naringin has a considerable hepatoprotective effect. The liver produces the protein albumin, which is essential for ligand transport and the maintenance of plasma oncotic pressure. Inflammatory diseases, chronic liver disease, and malnutrition can all be confirmed by low albumin levels. Compared to rats in the normal control group, the disease control groups had considerably lower levels of albumin and total protein. Naringin therapy dramatically brought the liver function indicators back to almost normal levels. Total protein (IV: 2.52 [0.53, 4.52] at 95% CI, p = 0.01, I² = 79%) ([Fig. 2 H]), albumin (IV: 1.82 [0.77, 2.87] at 95% CI, p = 0.0007, I² = 72%) ([Fig. 2 M]), and LDL and cholesterol levels that were elevated in disease control were brought down by treatment with naringin where LDL (IV: − 1.81 [− 3.13, − 0.50] at 95% CI, p = 0.007, I² = 57%) ([Fig. 2 K]) showed no drastic reduction in comparison to disease control, while elevated levels of cholesterol (IV: − 2.51 [− 4.52, − 0.50] at 95% CI, p = 0.01, I² = 86%) ([Fig. 2 I]) showed significant reduction; the levels of HDL (IV: 12.34 [− 9.72, 34.41] at 95% CI, p = 0.27, I² = 97%) ([Fig. 2 L]), which were decreased in disease control, were improved with naringin treatment but were not significant; elevated levels of triglyceride (IV: − 3.05 [− 3.85, − 2.25] at 95% CI, p < 0.00 001, I² = 0%) ([Fig. 2 J]) were significantly brought down to near normal with naringin treatment. It has been demonstrated that nitric oxide and inducible nitric oxide synthase are important in liver disease. NO is a powerful vasodilator that controls blood flow and vascular tone, and iNOS is an enzyme that generates NO in response to several stimuli, such as infection and inflammation. Increased NO production in liver disorders is caused by elevated iNOS expression, which can have both beneficial and detrimental effects. NO content and the relative production of iNOS, which were increased in various disease models, were reduced by NAR treatment. There was an insignificant reduction in NO levels after NAR treatment (IV: − 2.32 [− 4.80, 0.16] at 95% CI, p = 0.07, I² = 82%) ([Fig. 2 N]). However, iNOS levels after NAR treatments show a significant reduction in iNOS expression owing to the hepatoprotective effect (IV: − 4.93 [− 7.01, -2.84] at 95% CI, p < 0.00 001, I²= 25%) ([Fig. 2 G]). These results are illustrated in [Fig. 2 A–N].

Fig. 2 Effect of Naringin on Biochemical Parameters.

Effect of naringin on morphological parameters

There was a noticeable drop in body weight when comparing the disease control group to the normal control. However, when compared to the normal control group, the disease control groupʼs liver mass increased drastically. Treatment with naringin showed a significant increase in body weight, whereas relative liver weight was significantly decreased in comparison. There was a significant improvement in liver weight (IV: − 2.77 [− 4.57, − 0.98] at 95% CI, p = 0.002, I² = 86%) ([Fig. 3 A]), and the improvement in body weight was insignificant (IV: 0.78 [− 0.36, 1.92] at 95% CI, p = 0.18, I² = 70%) ([Fig. 3 B]) in the naringin treatment group as compared to the disease control group. These results are illustrated in [Fig. 3 A] and [B].

Fig. 3 Effect of Naringin on Liver Morphological Parameters.

Effect of naringin on oxidative stress markers

A clear indication of the disparity between oxidants and antioxidant levels is evident in the pathophysiology of several hepatic diseases. Numerous published studies on the hepatoprotective effects of naringin have shown that the disease control groupʼs levels of enzymatic and non-enzymatic antioxidants were drastically different from those of the normal control group. Naringin treatment has drastically reduced the production of free radicals and oxidative stress, leading to a drastic improvement in GSH (IV: 2.80 [1.68, 3.91] at 95% CI, p < 0.00 001, I² = 81%), catalase (IV: 3.95 [1.80, 6.11] at 95% CI, p = 0.0003, I²= 85%), GPx (IV: 3.15 [2.19, 4.11] at 95% CI, p < 0.00 001, I² = 68%), GST (IV: 4.21 [1.37, 7.04] at 95% CI, p = 0.004, I² = 89%), GR (IV: 3.50 [1.60, 5.40] at 95% CI, p = 0.0003, I² = 67%), SOD (IV: 3.10 [1.84, 4.36] at 95% CI, p < 0.00 001, I² = 86%), and TBARS (IV: − 4.31 [− 6.79, − 1.83] at 95% CI, p = 0.0007, I² = 84%), LPO/MDA (IV: − 3.80 [− 5.07, − 2.54] at 95% CI, p < 0.00 001, I² = 79%), which were close to normal levels compared with disease control. These results are shown in [Fig. 4 A–H].

Fig. 4 Effect of Naringin on Antioxidant Parameters.

Sensitivity analysis

[Fig. 2 O] depicts the results of total bilirubin when sensitivity analysis was performed by removing the study Esuola et al. [10]. The sensitivity analysis yielded a more significant outcome (IV: − 2.51 [− 3.71, − 1.32] at 95% CI, p < 0.0002 I² = 78%), reiterating the hepatoprotective effect of Naringin.

[Fig. 2 P] depicts the results of albumin when sensitivity analysis was performed by removing the study Hassan RA et al. [19]. The sensitivity analysis yielded a more significant outcome: albumin (IV: 2.18 [1.46, 2.90] at 95% CI, p < 00 001 I² = 26%). [Fig. 2 Q] depicts the results of cholesterol when sensitivity analysis was performed by removing the study Mahdavinia M et al. [24]. The sensitivity analysis yielded a more significant outcome in cholesterol (IV: − 3.22 [− 4.73, − 1.71] at 95% CI, p < 0.0001, I² = 63%); [Fig. 2 R] depicts the results of HDL when sensitivity analysis was performed by removing the study Esuola et al. [10]. The sensitivity analysis yielded no significant change with HDL results (IV: 20.78 [− 6.11, 47.67] at 95% CI, p = 0.13, I² = 94%).

[Fig. 3 C] depicts the results of body weight when sensitivity analysis was performed by removing the study Mahdavinia et al. [24]. A significant level of hepatoprotection was observed in body weight (IV: 1.23 [0.15, 2.31] at 95% CI, p = 0.03, I² = 53%) when sensitivity analysis was performed, indicating that the excluded study affected the outcome of the study.

[Fig. 4I] depicts the results of SOD when sensitivity analysis was performed by removing the studies Akamo et al. [12] and Rodriguez et al. [26]. It was observed that the outcome SOD (IV: 3.74 [2.64, 4.84] at 95% CI, p < 0.00 001 I² = 77%) remained significant regardless of the two studies that we excluded for sensitivity analysis. [Fig. 4 J] depicts the results of CAT when sensitivity analysis was performed by removing the study Rodriguez et al. [25]: catalase (IV: 4.72 [3.03, 6.42] at 95% CI, p < 0.00 001, I² = 73%). The sensitivity analysis yielded a more significant outcome. [Fig. 4 K] depicts the results of GST when sensitivity analysis was performed by removing the study Akamo et al. [12]: GST (IV: 5.33 [2.57, 8.09] at 95% CI, p = 0.0002, I² = 80%). The sensitivity analysis yielded a more significant outcome.

Effect of naringin on inflammatory mediators

Inflammatory mediators have a major role in diseases that are linked to inflammation, such as fatty liver diseases or alcoholic liver disease, because they can alter the immune system, have an impact on tissue remodelling, and cause the emergence of liver disorders. These molecules influence the progression and intensity of the disease by inducing inflammation, fibrosis, and hepatic cell death. When compared with normal control, the disease control groupʼs levels of inflammatory mediators were noticeably higher. Treatment with naringin showed a significant decrease in interleukine-1β (IV: − 9.60 [− 12.42, -6.78] at 95% CI, p < 0.00 001, I² = 0%) ([Fig. 5 A]), interleukin-6 (IV: − 6.80 [− 9.21, − 4.39] at 95% CI, p < 0.00 001, I²= 74%) ([Fig. 5 B]), and TNF-α (IV: − 5.03 [− 7.42, − 2.63] at 95% CI, p < 0.0001, I² = 79%) ([Fig. 5 C]), but not NF-κB (IV: − 14.52 [− 40.12, 11.07] at 95% CI, p = 0.27, I² = 94%) ([Fig. 5 D]) in which the decreases in NF-κB levels were not significant in contrast to the disease control group. These results are illustrated in [Fig. 5 A–D].

Fig. 5 Effect of Naringin on Inflammatory Markers.

Effect of naringin on apoptosis markers

Apoptosis is inhibited by the anti-apoptotic protein Bcl-2 through the activation of caspases, which are proteases essential to the completion of apoptosis. On the contrary, Bax is a pro-apoptotic protein that triggers caspases to cause apoptosis. Therefore, a higher value of the Bax/Bcl-2 ratio is indicative of cell death in the disease control group. The naringin-treated group showed a significant reduction in Bax/Bcl-2 ratio (IV: − 9.59 [− 14.99, − 4.20] at 95% CI, p = 0.0005, I² = 54%) ([Fig. 6 A]) in contrast to the disease control. By cleaving a variety of cellular proteins, the essential executioner caspase-3 is activated during apoptosis and plays a crucial part in the execution phase of programmed cell death. Caspase-3 levels (IV: − 4.13 [− 5.90, − 2.36] at 95% CI, p < 0.00 001, I² = 54%) ([Fig. 6 B]) that were elevated in the disease control group were significantly brought down by naringin treatment. These results are illustrated in [Fig. 6 A] and [B].

Fig. 6 Effect of Naringin on Apoptosis Markers.

Histopathological investigations

Histopathological evaluations were performed using the haematoxylin and eosin (H&E) staining technique. In the included studies, except for a few studies that quantified the histological observations, other evaluations were qualitative. There are not enough quantitative data on histopathological examinations currently available for carrying out a meta-analysis. Therefore, the supplementary data file summarises histopathological findings in the treatment and control groups.

Discussion

This systematic review compiles empirical data that meets predetermined eligibility criteria and synthesises it to address a specific research question. A meta-analysis further enhances this process by statistically aggregating the findings, providing a quantitative summary of the results [30]. Naringin, a well-known phytochemical, has been extensively studied for its various biological activities, particularly its potential to reduce oxidative stress. This therapeutic effect is a key focus in experimental research exploring its hepatoprotective properties.

In this study, we performed a systematic review and meta-analysis (SR & MA) to evaluate the protective effects of naringin across a range of hepatic diseases and disorders, with a particular focus on those associated with oxidative stress and inflammation induced by external agents. A total of 20 articles were included, encompassing a wide array of preclinical research on naringin in various animal models, all selected according to predefined eligibility criteria. The primary mechanisms explored in these studies were oxidative stress and inflammation, which were central to the pathophysiology of the hepatic diseases investigated.

The research studies highlight naringinʼs diverse hepatoprotective effects against various forms of liver injury and toxicity. As a flavonoid predominantly found in citrus fruits, naringin has been extensively studied for its capacity to protect cells from chemical- and drug-induced inflammation and oxidative stress. Notably, naringin has shown potential in shielding the liver from toxicity associated with chemotherapeutic agents, including doxorubicin, cyclophosphamide, paclitaxel, and 5-fluorouracil. For instance, a study by Khaled et al. demonstrated that naringin effectively reduced elevated liver enzyme levels, bilirubin, and histological alterations induced by paclitaxel administration in rats [14]. Furthermore, research by Xi et al. and Gelen et al. illustrated that naringin could significantly attenuate liver and kidney damage induced by doxorubicin and 5-fluorouracil through the modulation of oxidative stress, inflammation, and apoptosis pathways [23], [27].

Naringin has also demonstrated hepatoprotective effects against toxicity induced by environmental pollutants and chemicals. Studies by Mahdavinia et al., Esuola et al., and Anis et al. reported that naringin attenuates liver damage caused by bisphenol A, lambda-cyhalothrin (a broad-spectrum synthetic pyrethroid insecticide), and di-n-butyl phthalate, respectively, primarily through its antioxidant and anti-inflammatory properties [10], [22], [24]. Furthermore, naringin has shown efficacy in protecting the liver from toxicity induced by pesticides, heavy metals, and other environmental toxins. Research by Pari and Amudha, as well as by Ali et al., highlighted that naringin could alleviate liver damage caused by nickel sulphate and lambda-cyhalothrin by reducing oxidative stress, inflammation, and metal accumulation in the liver [11], [15]. Additionally, naringin has exhibited hepatoprotective effects in animal models of metabolic liver diseases, including diabetes and non-alcoholic fatty liver disease (NAFLD). For example, a study by Rodriguez et al. demonstrated that naringin could mitigate liver dysfunction, oxidative stress, inflammation, and apoptosis associated with diabetes induced by streptozotocin administration [26].

Biomarkers of liver function

The assessment of liver function and health is critically dependent on the evaluation of key enzymes and biomarkers. As the primary site of activity for AST, ALT, and ALP, the liver plays a central role in amino acid metabolism and protein catabolism [31], [32]. Gamma-glutamyl transferase, predominantly localised in the liver, is integral to amino acid transport and glutathione metabolism. Elevated levels of these enzymes in the bloodstream are commonly used as reliable biomarkers of liver inflammation, injury, or damage, underscoring their importance in the clinical assessment of liver health [33].

The LDH, an enzyme present in the liver, as well as in other tissues, serves as a marker of tissue damage. Elevated LDH levels may reflect hepatocyte necrosis or damage, thereby providing valuable information for the evaluation of liver function [34], [35]. Additionally, serum albumin, a crucial protein synthesised by the liver, is an important indicator of liver function and overall health. Reduced albumin levels may suggest liver dysfunction, inflammation, or malnutrition, highlighting its relevance as a clinical biomarker for liver status [37].

Oxidative stress and antioxidant mechanisms

In this study, we gathered data to investigate the potential hepatoprotective properties of naringin, focusing on its ability to reduce oxidative stress, prevent cell death, and promote cell survival. Under conditions of oxidative stress, cells initiate a series of intracellular processes that generate highly reactive oxygen species. The NADPH oxidase enzyme, located within the mitochondria, catalyses the conversion of molecular oxygen into superoxide radicals, which subsequently combine with hydrogen ions to form hydrogen peroxide. This hydrogen peroxide then undergoes a Fenton reaction, interacting with superoxide radicals in the presence of divalent cations such as copper (Cu²⁺) or ferrous (Fe²⁺) ions, resulting in the production of highly reactive hydroxyl radicals (OH). These hydroxyl radicals can, in turn, react with nitrogen molecules, generating nitrosative free radicals [38], [39].

When oxidative and nitrosative free radicals interact with fatty acids in cell membranes, they initiate lipid peroxidation, leading to denaturation of the membrane. The extent of LPO can be assessed by measuring malondialdehyde levels. Additionally, free radicals can damage cellular macromolecules, including DNA, RNA, proteins, and lipids, contributing to molecular injury. The bodyʼs innate antioxidant defence system plays a crucial role in mitigating and neutralising free radicals. Enzymatic antioxidants such as SOD neutralise superoxide radicals, CAT converts hydrogen peroxide into water and oxygen, and glutathione peroxidase (GPx) catalyses reactions involving glutathione. Non-enzymatic antioxidants, including alpha-lipoic acid, ascorbic acid, and alpha-tocopherol, also help to inhibit LPO by utilising GSH. However, when internal antioxidant defences are compromised, external antioxidants may be required to counteract oxidative stress and prevent cellular damage. Naringin, a flavonoid derived from citrus fruits, is recognised for its antioxidant properties and mechanisms [39].

Non-enzymatic antioxidants like GSH and SOD provide the first line of defence against free radical toxicity, maintaining a balance with reactive oxygen species (ROS) essential for cellular health [40]. Drug-induced toxicity can disrupt this balance, highlighting the role of antioxidants in preventing oxidative stress [41], [42]. Naringin helps maintain membrane stability against drug-induced damage by regulating antioxidant levels and ROS production. The meta-analysis revealed that naringin treatment restores GSH levels, reduces LPO, and enhances SOD and GSH activity.

Lipids such as triglycerides and cholesterol, vital for liver metabolism, are regulated by the farnesoid X receptor (FXR), which, when activated, improves liver function [43], [44], [45], [46], [47], [48], [49], [50], [51]. Apoptosis, mediated by proteins like Bcl-2, Bax, and caspase-3, contributes to liver injury [52], [53], [54]. Naringin significantly reduces the Bax/caspase-3 ratio, indicating its protective effect against cell death. Nrf2 activation leads to the transcription of antioxidant response element (ARE)-regulated genes, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1) [55]. These enzymes play a critical role in scavenging reactive oxygen species (ROS) and reducing oxidative stress. Under normal conditions, Nrf2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1), which promotes its ubiquitination and degradation [56]. Upon exposure to oxidative stress, Keap1 undergoes conformational changes, releasing Nrf2, which then translocates into the nucleus to activate ARE-driven gene transcription [55], [56].

Our systematic review reveals that naringin acts as an Nrf2 activator, upregulating the expression of SOD, CAT, and GPx, thereby enhancing the liverʼs resilience to oxidative damage. Furthermore, naringin has been shown to suppress malondialdehyde (MDA) levels, a key marker of lipid peroxidation, suggesting its ability to maintain membrane integrity. The activation of Nrf2 by naringin indicates its potential to counteract oxidative stress-related hepatic disorders, including drug-induced liver injury and metabolic liver diseases such as non-alcoholic fatty liver disease (NAFLD) and so on [12], [16], [19], [20], [21], [24], [25], [26], [27].

Inflammatory mediators

Inflammatory mediators like tumour necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6) play roles in liver diseases. NF-κB, a transcription factor, regulates inflammation and cell survival genes. Naringinʼs modulation of these mediators suggests its potential as a therapeutic agent for liver diseases [57], [58], [59], [60].

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathway plays a pivotal role in regulating inflammatory responses by modulating the transcription of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) [57], [58], [59], [60], [61]. In chronic liver conditions, excessive activation of the NF-κB pathway leads to sustained inflammation, hepatocyte apoptosis, and fibrosis. Naringin has been reported to inhibit the phosphorylation and subsequent degradation of IκBα, a key inhibitor of NF-κB [61]. By stabilising IκBα, naringin prevents NF-κB translocation into the nucleus, thereby reducing pro-inflammatory cytokine expression. Studies have demonstrated that naringin administration significantly lowers TNF-α, IL-1β, and IL-6 levels, indicating its efficacy in modulating inflammation via NF-κB suppression. This highlights naringinʼs potential in mitigating liver injury caused by chemotherapeutic drugs, environmental toxins, and metabolic disorders.

The phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signalling pathway is crucial for cell survival, metabolism, and inflammation regulation. Dysregulation of this pathway contributes to hepatocyte apoptosis and fibrosis in liver diseases. The activation of PI3K leads to the phosphorylation of Akt, which in turn modulates downstream effectors such as mammalian target of rapamycin (mTOR), glycogen synthase kinase-3β (GSK-3β), and the Bcl-2 family of proteins [2], [62]. Akt activation enhances cell survival by inhibiting pro-apoptotic proteins like Bax and promoting anti-apoptotic proteins like Bcl-2.

Naringinʼs hepatoprotective effects extend to the modulation of the PI3K/Akt pathway. Studies have reported that naringin increases Akt phosphorylation, thereby promoting hepatocyte survival and reducing apoptosis. Additionally, naringin suppresses the activation of caspase-3, a key executioner of apoptosis, further confirming its protective role in preventing liver cell death. Given that PI3K/Akt also plays a role in lipid metabolism regulation, naringinʼs activation of this pathway suggests its potential to mitigate NAFLD progression by improving lipid homeostasis.

Clinical significance and mechanisms

The clinical significance of these models lies in their use to study the pathophysiology of various liver diseases and evaluate the potential therapeutic effects of natural compounds like naringin. These models mimic human conditions such as drug-induced liver injury, chemical/toxin-induced liver damage, metabolic liver diseases, and liver fibrosis. Findings from these studies provide insights into the mechanisms underlying liver damage and the protective action of natural antioxidants, which have important clinical implications. These models can estimate the effects of drug/chemical-induced toxicity in humans, as many of the toxins, drugs, and chemicals used to induce liver injury in these animal models are also relevant to human exposures and liver diseases. The protective effects of naringin demonstrated in these studies suggest its potential as a therapeutic agent for managing liver diseases in humans. The animal models mimic real-world human exposures and liver diseases, indicating that naringin could be a promising natural compound for developing new treatments to protect the liver and manage various liver disorders in people.

Conclusion

This systematic review and meta-analysis highlights naringinʼs effectiveness in reducing oxidative stress caused by various factors leading to hepatotoxicity or abnormal liver function. The findings suggest that both enzymatic antioxidants (SOD, catalase, GST, and GPx) and non-enzymatic antioxidants (GSH) support the hypothesis that naringin could be used to manage a range of hepatic disorders. Further studies with human patients are recommended to determine naringinʼs safety, efficacy, and therapeutic potential for human-liver-associated conditions. The compound demonstrates significant protective effects against liver injury and toxicity through its antioxidant, anti-inflammatory, and anti-apoptotic properties. Naringin effectively reduces liver enzyme levels, such as ALT, AST, and ALP, which are crucial markers of liver health. Additionally, it enhances antioxidant enzyme activity, including SOD, CAT, and GPx, while reducing lipid peroxidation and restoring glutathione levels. These actions help counteract oxidative stress and support the liverʼs natural defence mechanisms. The studies reviewed show naringinʼs efficacy in mitigating liver damage from various sources, including chemotherapeutic drugs, environmental pollutants, and metabolic disorders like diabetes and non-alcoholic fatty liver disease (NAFLD).

The clinical relevance of these findings is underscored by the use of animal models that closely mimic human liver diseases, providing insights into naringinʼs therapeutic applications. Naringin may offer therapeutic benefits in managing metabolic liver diseases by influencing lipid metabolism and apoptosis pathways, demonstrating broad-spectrum efficacy across different liver injury models. However, to fully understand its safety, efficacy, and mechanisms in human populations, further research is needed. Future studies should aim to standardise experimental methodologies, explore optimal dosing regimens, and assess naringinʼs therapeutic potential in clinical settings. This research is crucial for determining naringinʼs feasibility as a viable treatment option for liver-associated conditions, ultimately contributing to improved management and prevention strategies for human liver disorders.

Limitations

One of the primary limitations of this systematic review and meta-analysis is the qualitative nature of most histological evaluations, which makes them unsuitable for meta-analysis. Histological assessments are often descriptive and rely on visual examination of tissue samples, leading to subjective interpretations that cannot be easily quantified. An alternative approach is to report histopathological evaluations using pathological characteristic scoring or grading of histological findings, which can provide a more standardised and quantifiable method of assessment.

Additionally, functional assays such as pentobarbitone-induced sleeping time, which could offer insight into the functional status of the liver, are not widely conducted by many research groups. These assays assess liver function by measuring how long a sedative drug induces sleep in an animal model, providing indirect evidence of liver function and metabolism. Similarly, the expression and activity of cytochrome P450 enzymes, which are critical for drug metabolism and detoxification processes in the liver, are not extensively explored by many research groups. Understanding the changes in cytochrome P450 activity could provide valuable insights into the metabolic pathways involved in liver injury and the hepatoprotective mechanisms of naringin.

Furthermore, this meta-analysis revealed substantial heterogeneity among the existing studies, likely due to inherent variations in the hepatotoxicants used, including their nature, induction periods, and mechanisms of liver injury, as well as differences in species, dose ranges, and treatment durations. While this diversity introduces variability, it also underscores the complexity of biological systems and the necessity for broader applicability of research findings. Notably, despite these differences, naringin consistently demonstrated hepatoprotective activity across various models, highlighting its broad-spectrum efficacy. However, this consistency also raises important questions regarding the mechanisms underlying naringinʼs protective effects. Further investigation is essential to elucidate and validate these mechanisms, which could facilitate the tailored application of naringin in specific contexts of liver injury and enhance its therapeutic efficacy.

Authorʼs Perspective

This systematic review and meta-analysis highlight naringinʼs promising potential as a natural hepatoprotective agent, with consistent effects across various preclinical models. The meta-analysis of data shows that naringin effectively modulates oxidative stress, inflammation, and apoptosis, making it a strong candidate for treating liver diseases characterised by these mechanisms. By reducing liver enzyme levels and enhancing antioxidant defences, naringin demonstrates significant efficacy in protecting liver function. As researchers, we are encouraged by these findings and optimistic about translating them into clinical applications. However, well-designed clinical trials are necessary to confirm naringinʼs safety and efficacy in humans, and further studies should explore its molecular mechanisms and optimal dosing strategies. Overall, the evidence supports continued investigation into naringinʼs therapeutic potential for improving clinical outcomes in liver disorders.

Contributorsʼ Statement

Muhammed Fayaz – Literature search, methodology, data extraction, drafting the manuscript; GL Viswanatha – Conceptualization, study design, formal analysis, statistical analysis, critical review and revision of manuscript; Shylaja H – Literature search, data analysis, drafting thye manuscript; Nandakumar K – Conceptualization, Project supervision, critical reviews of protocol, data and manuscript.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgements

We thank Manipal College of Pharmaceutical Sciences (MCOPS), Manipal Academy of Higher Education (MAHE), Manipal, for providing the opportunity and support to conduct this systematic review and meta-analysis.

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Publication History

Received: 02 January 2025

Accepted after revision: 23 April 2025

Article published online:
14 May 2025