The Role of Antioxidants in the Treatment of Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review

Non-alcoholic fatty liver disease (NAFLD) is a global public health problem that causes liver-related morbidity and mortality. It is also an independent risk factor for non-communicable diseases. In 2020, a proposal was made to refer to it as “metabolic dysfunction-associated fatty liver disease (MAFLD)”, with concise diagnostic criteria. Given its widespread occurrence, its treatment is crucial. Increased levels of oxidative stress cause this disease. This review aims to evaluate various studies on antioxidant therapies for patients with MAFLD. A comprehensive search for relevant research was conducted on the PubMed, SCOPUS, and ScienceDirect databases, resulting in the identification of 87 studies that met the inclusion criteria. In total, 31.1% of human studies used natural antioxidants, 53.3% used synthetic antioxidants, and 15.5% used both natural and synthetic antioxidants. In human-based studies, natural antioxidants showed 100% efficacy in the treatment of MAFLD, while synthetic antioxidants showed effective results in only 91% of the investigations. In animal-based research, natural antioxidants were fully effective in the treatment of MAFLD, while synthetic antioxidants demonstrated effectiveness in only 87.8% of the evaluations. In conclusion, antioxidants in their natural form are more helpful for patients with MAFLD, and preserving the correct balance of pro-oxidants and antioxidants is a useful way to monitor antioxidant treatment.


Introduction
Non-alcoholic fatty liver disease (NAFLD) encompasses a range of liver conditions, from harmless non-alcoholic fatty liver (NAFL) to more severe non-alcoholic steatohepatitis (NASH) with or without fibrosis, NASH cirrhosis, and hepatocellular carcinoma (HCC) [1].NAFLD is a significant public health concern, as it is a leading cause of liver-related morbidity and mortality globally, and it is also an independent risk factor for non-communicable diseases [2].A combination of invasive and noninvasive tests is essential to diagnose NAFLD.The most comprehensive test for diagnosing and scoring fatty liver disease is a liver biopsy.The lesion at the most clinically benign end of the spectrum is fatty liver (hepatic steatosis).Both large (macro-) and microscopic (micro-) fat vesicles, mostly consisting of triglycerides, build up inside hepatocytes without significantly inducing scarring, liver cell death, or hepatic inflammation.The lesion at the other extreme end of the spectrum is mation, as well as activate many intracellular pathways, which might ultimately result in hepatocyte apoptosis [16].
Different results have been obtained regarding the effect of antioxidants, which requires discussion.This systematic review aims to collect information on the impact of antioxidants in the treatment of MAFLD.

Literature Search
In this packccsystematic review, the recommendations stated in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed.The systematic review protocol was registered in the PROSPERO database under the registration ID CRD42024534095, and a detailed exploration of the PubMed, SCOPUS, and ScienceDirect databases was performed.The primary sources of antioxidants are natural and dietary sources, as well as synthetic and medicinal supplements.Additionally, a search was performed using relevant keywords or title headings.Full details of the search strategy can be found in Table 1.
Table 1.Full details of the search strategy terms.

Study Selection
The inclusion and exclusion criteria for this review are described in Table 2.As an essential requirement for inclusion in the review, the research had to satisfy all established inclusion criteria.Publications were individually screened by two authors, KM and FF, to ensure compliance with the established inclusion criteria.Consequently, comprehensive reports were obtained for studies that indicated inconsistency or seemed to satisfy the inclusion criteria.Furthermore, disagreements were effectively resolved through an intensive evaluation process, resulting in the achievement of a consensus.On occasions when consensus could not be reached, the opinion of a third reviewer (SK) was sought.

Studies that apply other treatments along with antioxidants
Studies that provide an oral or injectable antioxidant intervention Studies that administer mixed nutrient supplementation where no group receives any specific antioxidant supplement alone Studies that administer a single antioxidant or a combination of antioxidants through supplementation or dietary intervention

Data Extraction and Quality Assessment
The reviewers autonomously extracted and documented data, including the author and publication year, population attributes such as sample size, antioxidant intervention (supplementation/dietary and medicinal forms), the duration of follow-up, postintervention status, and quality control score determined by the two independent reviewers.The studies were evaluated using a study design and sampling method suitable for research.The sample size was sufficient, taking into account the prevalence of MAFLD.The evaluation of the results was performed using approved criteria.The outcomes were analyzed impartially, and the response rate was adequate.The statistics were reported with confidence intervals, and detailed descriptions of the study subjects were provided.Ultimately, the quality assessment determined that the selected studies met all the specified criteria and could be considered acceptable.

Search Results
Figure 1 provides a concise overview of the procedure used to select pertinent studies.The search approach identified an overall number of 1015 articles.Furthermore, an additional 83 articles were found through an extensive review of the reference lists of pertinent reviews.Following the exclusion of duplicates, a total of 653 articles were selected based on their title and abstracts to determine their eligibility.A total of 445 articles were evaluated using their full texts, while 358 articles were removed due to factors such as untrustworthy study designs (including case reports, ethnographies, and observational designs), patient populations, interventions, outcome measurements, sample sizes smaller than 10, or the inaccessibility of the full text.As a result, a total of 87 articles were included in this review.
Among the animal studies, a total of 38 investigations, representing 90.4% of the studies, indicated considerable effectiveness of antioxidant therapy.On the contrary, in four studies (9.5%), no significant changes were detected between the antioxidant therapy group and the placebo group.Of the 38 studies that indicated significant effectiveness, 10 examined natural antioxidants, and 28 studies examined synthetic antioxidants.All four studies where no significant difference was seen examined synthetic antioxidants.The findings are summarized in Table 4.After duplicates were eliminated, 653 articles were chosen for eligibility according to their title and abstract.Of these, 445 articles underwent full-text evaluations; 358 articles were omitted due to faulty data.As a result, in this review, 87 publications were included, with 45 being human studies and 42 being animal studies.

Study Characteristics
Of the 45 human studies, 14 (31.1%)used natural antioxidants, 24 (53.3%)used synthetic forms of antioxidants in dietary supplements and medications, and 7 used natural and synthetic antioxidants.Of the 24 studies that studied synthetic forms of antioxidants, 14 (58.8%)used dietary supplements, 4 (16.6%)used medications, and 6 (25%) used both dietary supplements and medications.
Among the human studies, 43 (95.5%)revealed a considerable effectiveness of antioxidant therapy, while 2 (4.4%) did not find significant differences from the placebo group.Of the 43 studies that had a significant effect, 14 examined natural antioxidants, 22 examined synthetic antioxidants, and 7 examined both natural and synthetic antioxidants.Furthermore, the two studies where no significant difference was seen examined synthetic antioxidants.Also, 30 studies examined both genders (66.6%), 8 studies (17.7) and 1 study (2.2%) included only males and females, respectively, and 6 studies did not mention the gender of cases.In addition, most of the studies, 38 of 45, have been designed as experimental, while there were 4 human studies, and 3 other studies used both experimental and human study design.The findings are summarized in Table 3.
Of the 42 animal studies, 10 (23.8%) used natural antioxidants, and 32 (76.1%) studies used synthetic forms of antioxidants in dietary supplements and medications.Of the 32 studies that studied synthetic forms of antioxidants, 7 (21.8%)used dietary supplements, and 25 (78.1%)studies used medications.
Among the animal studies, a total of 38 investigations, representing 90.4% of the studies, indicated considerable effectiveness of antioxidant therapy.On the contrary, in four studies (9.5%), no significant changes were detected between the antioxidant therapy group and the placebo group.Of the 38 studies that indicated significant effectiveness, 10 examined natural antioxidants, and 28 studies examined synthetic antioxidants.All four studies where no significant difference was seen examined synthetic antioxidants.The findings are summarized in Table 4.The two groups mainly differed in anthropometrics, liver enzyme levels, and metabolic markers; however, the results of the routine therapies that both groups received may have concealed some of the differences.ALT-alanine transaminase; AST-aspartate transaminase; CR-calorie restricted; GGT-gamma-glutamyl transferase; GTE-green tea extract; HOMA-IR-Homeostatic Model Assessment of Insulin Resistance; IR-insulin resistance; MD-Mediterranean diet; NAFLD-non-alcoholic fatty liver disease; NASH-non-alcoholic steatohepatitis; n-3 PUFA-omega-3 polyunsaturated fatty acids; UDCA-ursodeoxycholic acid; T2DM-type 2 diabetes mellitus; FGE-garlic extract; FMD-flow-mediated dilation; NOX2-NADPH oxidase 2; FLD-fatty liver disease; GC-green cardamom; hs-CRP-high-sensitivity C-reactive protein; TNF-α-tumor necrosis factor alpha.The combined treatment of rosuvastatin and beta-carotene had a better effect on reducing fat accumulation in the liver than each drug alone.

Discussion
The present study was conducted as a systematic review to investigate the impact of antioxidant therapy on patients with MAFLD.This study investigated two types of antioxidants: natural antioxidants, found in fruits and vegetables, and synthetic antioxidants, such as dietary supplements or medications.
The analyzed studies indicate that natural antioxidants have a high level of efficacy in the treatment of MAFLD (100%).However, there is a scarcity of research using this method.The positive impact of synthetic antioxidants is not consistently observed, and only 91% of the studies demonstrate successful outcomes.On the basis of the available data, it may be inferred that natural antioxidants show greater efficacy than synthetic antioxidants in the treatment of MAFLD.Furthermore, fruits and vegetables are abundant in essential elements, as well as antioxidants.In contrast, previous studies have shown that the correct combination of minerals, such as sodium, potassium, selenium, magnesium, zinc, copper, and calcium, in conjunction with antioxidants, can improve the efficacy of antioxidants [104].
The impact of genetics on liver steatosis, inflammatory modifications, and fibrosis has been established by several studies.In genome-wide research, two genes have been associated with an increased risk of MAFLD: patatin-like phospholipase domain-containing 3 (PNPLA3) and trans-membrane 6 superfamily member 2 (TM6SF2) [9].Lean MAFLD is a condition where individuals demonstrate a fatty liver but a normal body mass index (BMI).The main risk factors for this disease are visceral obesity, insulin resistance, high cholesterol, fructose intake, and specific genes.The triacylglycerol lipase enzyme, which is produced by the PNPLA3 gene, regulates lipid hydrolysis and assists in preserving balance between energy and its utilization in adipose tissue.Steatosis, inflammation, fibrosis, and hepatocellular carcinoma (HCC) can all be caused by a particular SNP in this gene.However, patients with MAFLD have a significantly decreased hepatic gene expression of TM6SF2, a gene essential for the generation of very-low-density lipoprotein (VLDL) [105].An important gene, designated G-protein-coupled receptor 120 (GPR120), is present in hepatocytes, Kupffer cells, and adipocytes.It functions as a receptor for polyunsaturated fatty acids (PUFAs).Hepatocyte damage is the basis of abnormal liver function tests (LFTs) in individuals with the GPR120 270H mutation.Targeted by glitazone diabetes medications, PPARγ is frequently expressed in adipose tissue and influences both the arrival and departure of fatty acids to and from the liver, as well as the development of adipocytes.Liver steatosis is caused by these gene mutations [9].
Both in vitro and in vivo studies have shown that silybin or silibinin restores nicotinamide adenine dinucleotide+ (NAD+), a coenzyme essential for redox processes, by blocking poly (ADP-ribose) polymerase and triggering the SIRT1/AMP-activated protein kinase (AMPK) pathway.Reduced AMPK activity has been linked to the de novo lipogenesis process in MAFLD.Silybin's anti-inflammatory action is achieved through the activity of SIRT2.Supplementing NAD+ with silybin has been found to be beneficial in preserving SIRT2 activity.Silybin has been shown to inhibit endoplasmic reticulum stress and the activation of the NLRP3 inflammasome in mice with fatty liver disease associated with metabolic dysfunction fed a high-fat diet [106].
Vitamin C has been reported to reduce mitochondrial ROS production, elevate levels of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase, and enhance electron transport chain function in the liver.Vitamin C affects the balance of lipids and glucose and reduces visceral obesity and MAFLD by activating PPARα [9].
Multiple in vitro investigations on mouse and human adipocytes have shown that vitamin D has an anti-inflammatory impact by reducing the expression of chemokines and cytokines through the activation of p38 mitogen-activated protein (MAP) kinase and the NF-κB classical inflammatory pathway [9].
Vitamin E can boost antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase; conversely, it reduces pro-oxidant contributions such as cellular myelocytomatosis (c-myc) and transforming growth factor-alpha (TGF-α), nitric oxide synthase, and NADPH.The antisteatotic activity of this substance is due to its capacity to decrease fatty acid uptake by hepatocytes via the downregulation of the hepatic cluster of differentiation 36 (CD36) protein, thereby limiting the amount of lipids available for peroxidation.Vitamin E reduces hepatic inflammation and fibrosis by downregulating the expression of pro-apoptotic BCL2 associated X (BAX), TGF-β, cyclooxygenase-2 (COX-2), and matrix metalloproteinase-2 (MMP-2) genes [1].
Plant flavonoids contain the naturally occurring flavonoid molecule quercetin.Quercetin's antibacterial, anticancer, and antioxidant activities protect against free radicals, in addition to providing pharmacological advantages.One of the most abundant and substantial sources of quercetin is acacia rice.Numerous studies have demonstrated the effectiveness of quercetin, a flavonoid with potent antioxidant properties, in reducing lipid accumulation and the expression of SREBP1c and XBP-1 in adipocytes.A direct antilipogenic impact is produced by inhibiting the DNL pathway through its effects on the AMPK pathways [107].
Turmeric contains a polyphenolic compound known as curcumin, which has a number of medicinal effects, including anti-inflammatory, antiproliferative, antioxidant, and antiangiogenic effects.According to research, curcumin may prevent mice from developing MAFLD caused by high-fat and high-fructose diets.By regulating the LXR pathway, curcumin inhibits the expression of cytochrome P4503A (CYP3A) and cytochrome P4507A (CYP7A).Additionally, by inhibiting the FAS and Nrf2 pathways, it decreases the expression of CD36, SREBP1c, and the small heterodimer partner (SHP), which decreases hepatic steatosis.In an in vitro study, curcumin was found to reduce the development of liver fat by preventing citrate transport in the AMPK pathway, regulating the aberrant expression of SLC13A5/ACL.This prevents citrate from being carried or broken down.Curcumin inhibits the expression of SREBP1c and the suppressor of cytokine signaling 3 (SOCS-3), and it increases the phosphorylation of the hepatic activator of transcription 3 (STAT3), preventing liver steatosis.This assists in decreasing hepatic fat accumulation and regulating lipid metabolism [107].A previous study demonstrated that, by enhancing the expression of the tight junction protein occludin 1, curcumin improved intestinal barrier function in MAFLD mice.The results of this study showed that it inhibited p65 nuclear translocation and NF-θB DNA-binding activity and that it decreased the expression of myeloid differentiation factor 88 (MyD88) in the liver, which, in turn, decreased hepatic steatosis [108].MAFLD development is influenced by PPAR gene methylation.Curcumin significantly reduced methylation levels, elevated PPAR protein expression, and significantly reduced fat storage in MAFLD rats in other studies [109].Curcumin protects LO2 cells from oleic acid-induced MAFLD by increasing the activity of certain proteins such as pAKT and P13K.Through Nrf2 signaling, it increases the absorption of glucose by liver cells and reduces NO and ROS levels.The initial phases of clinical trials have indicated that an excessive amount of 12 g/day of curcumin is safe for human intake.Because of its high metabolism and insufficient absorption, it has a low bioavailability.Currently, research is being conducted to increase the drug's bioavailability and make it an unprecedented medication [107].
Resveratrol is a phenolic molecule that belongs to the stilbene family of phenols.It has a structure of C6-C2-C6 and is commonly found in plants such as cassia seeds, grape skins, and white tea.The substance comes primarily from the rhizome extract of Polygonum multiflorum.Resveratrol exhibits potent antioxidant, anticancer, and anti-inflammatory properties.Research has shown that resveratrol stimulates the sirtuin pathway (STRT1) for the treatment of MAFLD.Resveratrol reduces fat storage by activating the STRT1-FOXO1 pathway, which prevents SREBPE-1c acetylation and decreases metabolic abnormalities.A reduction in STRT1 levels in hepatocytes can lead to liver inflammation [110].The stimulation of 3T3-L1 cells with TNF-α leads to an increase in cytokine mRNA expression through the siRNA-mediated activation of SIRT1 [107].Meanwhile, elevated SIRT1 levels suppress the generation of pro-inflammatory cytokines such as NF-κB and TNF-α, thus protecting the liver's metabolism from the harm caused by a high-fat diet.Research has shown that resveratrol can decrease apoptosis, mitochondrial dysfunction, and reactive oxygen species (ROS) production in OA-induced L02 cells.It can treat metabolic dysfunction-associated fatty liver disease (MAFLD) by decreasing caspase-3 and p53 and increasing B-cell lymphoma 2 (Bcl-2) levels, which helps to reduce liver fat accumulation [111].The molecular mechanisms of non-alcoholic fatty liver disease (NAFLD) mediated by antioxidants in humans is summarized in Figure 2.
In this context, these medications may have additive or synergistic effects on the target.Furthermore, the inclusion of a drug can potentially lead to a reduction in the dosage of other medication, thereby improving safety.It should be noted that the inclusion of a drug may reduce the negative consequences associated with an otherwise efficacious drug [119,120].Furthermore, many fruits and vegetables, such as oranges, contain potassium and calcium, which have the potential to effectively manage blood pressure.On the basis of the evidence mentioned above, it can be inferred that the natural antioxidants present in fruits and vegetables may demonstrate greater effectiveness [104].It is possible that medicinal supplements contain a combination of ingredients consisting of natural antioxidants that are effective.This study also highlights the absence of other comparable studies investigating the efficacy of antioxidants in preventing MAFLD in at-risk groups.
Furthermore, in 4.4% of the studies analyzed, there was no statistically significant impact on patient improvement when antioxidants were used.Furthermore, the reviewed studies also indicated that the efficacy of antioxidant therapy was not significantly influenced by the dosage or duration of treatment.
In the present systematic review, a study of animal research was also conducted.The reviewed animal studies showed that natural antioxidants are thoroughly effective in treating MAFLD (100%), but few studies used this method.This beneficial effect was not consistently seen with synthetic antioxidants, and only 87.8% of the studies showed effective results.On the basis of these data, it can be assumed that antioxidants may be more effective in their natural form than in a synthetic form in treating MAFLD.
Feeding a high-fat diet (HFD) to mice leads to the accumulation and fibrosis of liver collagen.Ascorbic acid supplementation decreases collagen levels and the mRNA expression of TGF-β and collagen.It also inhibits hepatocyte apoptosis and liver injury by increasing Bcl-2 protein levels and decreasing caspase 8.It effectively reduces liver inflammation in obese mice by suppressing the expression of inflammatory genes, including TNFα and MCP-1, in hepatocytes [112].
By controlling the proteins involved in lipid homeostasis, in which CES1 activation plays a crucial role, vitamin E in mice reduces the effects of a high-fat diet on liver lipid accumulation and glucose homeostasis.The biochemical mechanism responsible for the vitamin E-mediated overexpression of CES1 is, at least partially, the activation of nuclear Nrf2 [113].
Quercetin may help HFD-fed mice overcome MAFLD.An HFD causes fat peroxidation, ferroptosis, and fat accumulation; therapy clearly reverses these effects.For example, quercetin inhibits ferroptosis by increasing the expression of anti-glutathione peroxidase four (GPX4) and decreasing the expression of anticyclooxygenase 2 (COX2) and the longchain family member acyl-coenzyme A synthase four (ACSL4) [114].
The administration of resveratrol to obese mice improves liver steatosis by improving glycolipid metabolic parameters, liver histology, inflammation, and lipid content.It could potentially have further positive effects by increasing T-SOD and GPX activities, inhibiting TNF-α production, suppressing TLR4 and CD36 expression [115], and improving steatohepatitis through the inhibition of the NF-jB inflammation pathway by further activating the AMPKa-SIRT1 pathway [116].The molecular mechanisms of non-alcoholic fatty liver disease (NAFLD) mediated by antioxidants in animals is summarized in Figure 3.

Current Limitations of Knowledge on the Effectiveness of Antioxidants in Treating MAFLD and Their Prospects
Although some evidence suggests the possible advantages of antioxidants for MAFLD, there are still certain issues that need to be clarified.First, because the vast majority of studies had an average duration of less than six months or 1 year, there has been an absence of substantial and outstanding scientific evidence indicating the longterm advantages of MAFLD antioxidant treatment.Second, it is currently questionable whether the general population and specific populations, such as men and women, the elderly, those with diabetes mellitus, children, and adolescents, should be prescribed antioxidant treatment.Third, how does long-term use of this antioxidant treatment affect In general, research examining the impact of antioxidants on the improvement of the condition of patients with MAFLD reveals contradictory results.On the contrary, the observed contradiction related to antioxidant properties in MAFLD therapy could also be attributed to the oxidative impact of antioxidants.Research has shown that, when the concentration of antioxidants in the human body is above the necessary threshold, oxidative effects are increased.In addition, an excess of antioxidants can contribute to elevated levels of oxidative stress [117].Therefore, despite the positive therapeutic perspective of antioxidant supplements, it is essential to exercise caution and avoid their indiscriminate and/or excessive administration.The cellular intrinsic antioxidant system provides protection against damage caused by oxidants.Therefore, an assessment of the pro-oxidant-antioxidant balance can serve as an effective strategy for the management of antioxidant therapy.Measurement of oxidant and antioxidant capacity has been shown to facilitate the understanding of their balance.As a result, the administration of antioxidants may provide greater efficacy in patients when considering the balance or ratio between pro-oxidants and antioxidants [110,118].
The efficacy of antioxidants as an alternative therapy for MAFLD may be limited due to its multifactorial nature.The use of supplementary treatments based on the patient's underlying disease, in conjunction with a suitable dose of antioxidants, appears to result in greater efficacy.The concept of combination therapy is interesting because it allows for the simultaneous targeting of multiple pathologic contributors to the disease.In the context of hepatic fibrosis, combination drugs can also be used to address the same target.In this context, these medications may have additive or synergistic effects on the target.Furthermore, the inclusion of a drug can potentially lead to a reduction in the dosage of other medication, thereby improving safety.It should be noted that the inclusion of a drug may reduce the negative consequences associated with an otherwise efficacious drug [119,120].Furthermore, many fruits and vegetables, such as oranges, contain potassium and calcium, which have the potential to effectively manage blood pressure.On the basis of the evidence mentioned above, it can be inferred that the natural antioxidants present in fruits and vegetables may demonstrate greater effectiveness [104].It is possible that medicinal supplements contain a combination of ingredients consisting of natural antioxidants that are effective.This study also highlights the absence of other comparable studies investigating the efficacy of antioxidants in preventing MAFLD in at-risk groups.

Current Limitations of Knowledge on the Effectiveness of Antioxidants in Treating MAFLD and Their Prospects
Although some evidence suggests the possible advantages of antioxidants for MAFLD, there are still certain issues that need to be clarified.First, because the vast majority of studies had an average duration of less than six months or 1 year, there has been an absence of substantial and outstanding scientific evidence indicating the long-term advantages of MAFLD antioxidant treatment.Second, it is currently questionable whether the general population and specific populations, such as men and women, the elderly, those with diabetes mellitus, children, and adolescents, should be prescribed antioxidant treatment.Third, how does long-term use of this antioxidant treatment affect people's health?The essential concern is to assess who will benefit the most from an antioxidant treatment for MAFLD based on their personal characteristics, especially those with overlapping health conditions.Fourth, it is challenging to determine consistent findings because the included studies varied according to the characteristics of their study structure, patient demographics, antioxidant types, dosages, and treatment durations.Fifth, confounding variables can affect the results and make it challenging to differentiate between the impact of antioxidants.These variables include differences in the initial characteristics of the study participants, lifestyle factors, and concurrent treatments.Sixth, data analysis may be limited by the variations in the methods used by studies to assess and present outcomes associated with antioxidant levels, metabolic parameters, and liver function.

Conclusions
Antioxidants have been indicated to have similar effects on humans and animals.These effects include regulating the SIRT1/AMPK, NFKB, and LXR pathways; decreasing the expression of proapoptotic genes such as BAX, inflammatory genes such as TNF-α, as well as TGF-β and COX2 genes; inhibiting the FAS and NrF2; and activating PPARα.Although natural antioxidants may be beneficial in treating MAFLD patients, combination therapy has been demonstrated to be more effective.However, more research is required to completely comprehend the effect of natural antioxidants.To improve the efficacy of MAFLD treatment, it is essential to take into account two crucial criteria.An effective approach to controlling treatment with antioxidants involves evaluating the appropriate balance between pro-oxidants and antioxidants.In essence, the administration of antioxidants at a suitable dose improves their efficacy, indicating the need for the development of customized therapeutic approaches.Furthermore, it is highly recommended to use the ideal dose of antioxidants in conjunction with other medications, such as antihypertensives, hypoglycemic agents, antidiabetic agents, and other cholesterol-balancing therapies, to effectively treat the underlying condition in patients with MAFLD.

Figure 1 .
Figure 1.PRISMA flow diagram showing the study selection and identification.A total of 1015 publications were identified, with 535 articles in the human studies category and 480 articles in the animal studies category.By looking through the reference lists of pertinent reviews, an additional 83 publications were found, 38 of which were animal studies and 48 of which were human studies.After duplicates were eliminated, 653 articles were chosen for eligibility according to their title and abstract.Of these, 445 articles underwent full-text evaluations; 358 articles were omitted due to faulty data.As a result, in this review, 87 publications were included, with 45 being human studies and 42 being animal studies.

Figure 1 .
Figure 1.PRISMA flow diagram showing the study selection and identification.A total of 1015 publications were identified, with 535 articles in the human studies category and 480 articles in the animal studies category.By looking through the reference lists of pertinent reviews, an additional 83 publications were found, 38 of which were animal studies and 48 of which were human studies.After duplicates were eliminated, 653 articles were chosen for eligibility according to their title and abstract.Of these, 445 articles underwent full-text evaluations; 358 articles were omitted due to faulty data.As a result, in this review, 87 publications were included, with 45 being human studies and 42 being animal studies.

Figure 3 .
Figure 3.The molecular mechanisms underlying the regression of non-alcoholic fatty liver disease (NAFLD) mediated by antioxidants in animals.In animal studies, antioxidants have been shown to improve this disease by affecting the expression of various genes in hepatocytes through molecular pathways, for example, by reducing the expression of inflammatory genes such as TNFα and MCP-1, as well as reducing the expression of TGF-βmRNA or the overexpression of CES1.MAFLDmetabolic dysfunction-associated fatty liver disease; TNF-α-tumor necrosis factor alpha; MCP-1monocyte chemoattractant protein-1; TGF-β-transforming growth factor beta; CES1carboxylesterase 1.

Figure 3 .
Figure 3.The molecular mechanisms underlying the regression of non-alcoholic fatty liver disease (NAFLD) mediated by antioxidants in animals.In animal studies, antioxidants have been shown to improve this disease by affecting the expression of various genes in hepatocytes through molecular pathways, for example, by reducing the expression of inflammatory genes such as TNFα and MCP-1, as well as reducing the expression of TGF-βmRNA or the overexpression of CES1.MAFLD-metabolic dysfunction-associated fatty liver disease; TNF-α-tumor necrosis factor alpha; MCP-1-monocyte chemoattractant protein-1; TGF-β-transforming growth factor beta; CES1-carboxylesterase 1.

Table 2 .
Inclusion and exclusion criteria.

Table 3 .
The summarized results of human studies that fulfilled the inclusion criteria.

Table 4 .
Summarized data of animal studies.