Zenan Hu
Hanxun Yue
Na Jiang
Liang Qiao
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- 1The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- 2Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- 3School of Public Health, Lanzhou University, Lanzhou, China
- 4Storr Liver Centre, Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia
Globally, metabolic dysfunction-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), is a common chronic liver disease. The progression of MAFLD leads to a vicious cycle in which oxidative stress results from the disease that is augmenting de-novo lipid levels and increases steatosis. Most non-enzymatic antioxidants are present in food. Therefore, the present review summarizes the findings of studies on food-derived antioxidants and presents an oxidative stress-related regulatory network in MAFLD, offering new ideas for MAFLD prevention and treatment.
1 Introduction
Metabolic dysfunction-associated fatty liver disease (MAFLD) is characterized by the presence of fat in ≥5% hepatocytes, independent of excess alcohol consumption and other chronic liver diseases (1, 2). Previously referred to as non-alcoholic fatty liver disease (NAFLD), the term MAFLD was introduced to encompass the metabolic factors driving this disorder (3). Some experts alternatively refer to it as metabolic dysfunction-associated steatotic liver disease (MASLD) (4, 5). For consistency, this review refers to the condition as MAFLD.
MAFLD primarily arises from the accumulation of lipids in hepatic cells and presents as a spectrum of conditions ranging from simple steatosis to steatohepatitis. This disease can be classified into two subtypes: metabolic dysfunction-associated fatty liver (MAFL), marked by hepatic steatosis without significant liver injury; metabolic dysfunction-associated steatohepatitis (MASH), characterized by hepatocyte damage, inflammatory cell infiltration, and hepatic cell death (6). Although often clinically perceived benign, MAFLD can advance to severe liver fibrosis, ultimately resulting in cirrhosis or hepatocellular carcinoma (HCC). During this progression, lipid accumulation induces mitochondrial dysfunction and oxidative stress, leading to hepacyte damage (7, 8). From 2016 to 2019, the global prevalence of MAFLD rose from 25% to approximately 30%, with the mortality rate increasing from 0.77/1000 to 1.65/1000 person-years, underscoring its significance as a leading cause of chronic liver disease-related morbidity and mortality worldwide (9). Moreover, MAFLD is strongly associated with metabolic syndrome, type 2 diabetes mellitus, atherosclerotic cardiovascular disease, and colorectal neoplasms (10, 11).
A central mechanism driving MAFLD progression is oxidative stress, which results from an imbalance between the production and elimination of reactive oxygen species (ROS) (12–15). This imbalance leads to accumulations of ROS, directly injuring hepatocytes and producing toxic metabolites like malondialdehyde (1). Moreover, oxidative stress creates a feedback loop that exacerbates lipid accumulation and steatosis, further amplifying MAFLD progression (16). The severity of MAFLD correlates with oxidative stress levels and oxidative stress is a potential diagnostic marker for MAFLD (17).
Extensive research has explored the mechanism of oxidative stress inducing MAFLD (18). Early work by Maurizio and Novo (19) identified the role of Nrf1 in linking oxidative stress to MAFLD by demonstrating that Nrf1-induced CYP4A upregulation increases ROS generation and inhibits antioxidant activity through suppression of ARE expression. Similarly, AHR has been implicated in MAFLD pathogenesis through its regulation of CYP1A1, influencing oxidative stress pathways (20). Recent studies have highlighted the role of genetic factors, such as SIRT5 rs12216101 T > G, in amplifying oxidative stress in MAFLD patients (21). Additionally, several miRNAs and ncRNAs have been recognized as crucial regulator of oxidative stress in MAFLD (22–24). Until now, Nrf2 emerges as a key molecule in modulating oxidative stress in MAFLD (25).
Dietary and lifestyle factors play a pivotal role in MAFLD progression (26–28). The oxidative balance score (OBS), which integrates pro- and antioxidant components from diet and lifestyle, has been shown to reflect the overall oxidative stress burden. Higher OBS was significantly associated with a lower risk of MAFLD (29). Real-world OBS analyses demonstrate that adopting a healthy diet and lifestyle, independently or in combination, can mitigate oxidative stress and significantly lower MAFLD onset and development (30). However, the precise role of diet in linking oxidative stress to MAFLD remains inadequately understood. We reviewed studies on food-derived antioxidants from the past decade, summarized representative research, and depicted a regulatory network targeting oxidative stress, centered on Nrf2 and mediated by endogenous molecules and signaling pathways. This review examined the impact of diet on oxidative stress, providing insights into potential preventive and therapeutic strategies for MAFLD.
2 Fruits, vegetables, grains, and herbs play a major role in alleviating oxidative stress
Many substances in fruits, vegetables, and grains can directly or indirectly inhibit MAFLD progression by suppressing oxidative stress. According to Li et al. (31), hesperetin, a flavonoid present in citrus fruits, boosted the antioxidant activity by triggering the PI3K/Akt pathway and reduced ROS overproduction by activating the Nrf2 pathway during MAFLD progression. Fan et al. reported that nobiletin, a polymethoxylated flavone primarily extracted from citrus peels, accelerated the dissociation of the Keap1-Nrf2 complex and promoted Nrf2 nuclear translocation, thereby alleviating MAFLD (32). In another study, total flavonoids extracted from Citrus changshan-huyou were reported to alleviate oxidative stress in MAFLD by upregulating miR-137-3p expression, which subsequently downregulated NOXA2/NOX2, reducing ROS generation (33). Found abundantly in apples, phloretin (a dihydrochalcone phenolic compound), alleviated oxidative stress by regulating the ERK/Nrf2 pathway, which enhanced the antioxidant response (34, 35). Extracted from blueberries and grapes, pterostilbene was showed to alleviate oxidative stress and enhance fatty acid metabolism and decomposition via activation of the AMPK/mTOR pathway in hepatocytes (36). Euterpe oleracea Mart, popularly known as açai, is a palm tree fruit usually found in the Brazilian Amazonas and Pará states. The aqueous extract of açai (AAE) significantly prevented oxidative stress in patients with MAFLD (37).
Apigenin, a naturally occurring flavonoid in various fruits and leafy vegetables, activated the Nrf2 signaling pathway to reduce oxidative stress, thereby attenuating MAFLD (38). Liensinine is an isoquinoline alkaloid commonly found in Nelumbo nucifera Gaertn (lotus seeds) which is often consumed in Asia. Liensinine was shown to inhibit oxidative stress by upregulating Nrf2 and modulating the AMPK signaling pathway by TAK1 activation (39). Oligosaccharides, extracted from Porphyra yezoensis (a commonly consumed algea in East Asia), alleviated oxidative stress by downregulating the TGF-β signaling pathway, which is implicated in liver inflammation and fibrosis (40).
A major flavonoid found in buckwheat, rutin alleviated oxidative stress in diabetes-associated MAFLD through the AMPK signaling pathway, which plays a crucial role in energy homeostasis and stress response (41, 42). Betaine is commonly found not only in beets and whole grains but also in shrimps and shellfish. It could regulate lipid metabolism and mitochondrial function as well as inhibit oxidative stress, making it a promising candidate for MAFLD prevention and treatment (43).
Some traditional Chinese herbs may be used as condiments in food. Aescin, a bioactive compound derived from the ripe dried fruits of Aesculus chinensis Bunge, ameliorated oxidative stress, thus exerting a curative impact on MAFLD. The mechanism underlying aescin’s action was that it interacted with Keap1, leading to an enhanced translocation of Nrf2 into the nucleus (44). Alpinetin is a novel plant flavonoid isolated from Alpinia katsumadai Hayata, which inhibited oxidative stress by enhancing SOD1/HO-1/Nrf2 expression in MAFLD (45). Safranal is the active constituent of saffron (B.O.: Crocus sativus). Sabir et al. demonstrated that safranal treatment reduced the levels of oxidative stress indicators in MAFLD animal models (46). Rhamnetin extracted from Rhamnus davurica Pall exhibited antioxidative properties, which were effective against steatohepatitis and hepatocellular carcinoma (47).
3 Animal foods and supplements have inhibitory effects on oxidative stress
Astaxanthin presents in shrimp, crab, salmon, algae, and other marine organisms. As a carotenoid, astaxanthin works by neutralizing ROS and reducing oxidative stress (48). Wu et al. (49) found that astaxanthin attenuated mitochondrial dysfunction by upregulating FGF21/PGC-1α, thus alleviating oxidative stress in MAFLD (50). Moreover, astaxanthin has been proved to more advantageous than vitamin E in reversing steatohepatitis (51). Omega-3 fatty acids exist in several forms and are abundantly present in oily fish (26). According to a systematic review, omega-3 polyunsaturated fatty acids were effective in counteracting oxidative stress in early-stage MAFLD (52).
López-Oliva et al. (53) showed that α-lactalbumin, found in dairy products, induced oxidative stress by upregulating XRαβ/SREBP-1-c/PPARγ expression and diminishing PPARα/CPT-1 expression and AMPKα phosphorylation. However, Chen et al. (54) reported that the α-lactalbumin peptide Asp-Gln-Trp (DQW) might serve as an effective dietary supplement for alleviating MAFLD by reducing oxidative stress (53). Additionally, the α-lactalbumin peptide Gly-Ile-Asn-Tyr (GINY) alleviated oxidative stress in MAFLD progression (55). As bacteriological studies have advanced, probiotics have been found to inhibit oxidative stress in MAFLD (56). Lactobacillus rhamnosus GG, a probiotic frequently found in dairy products such as cheese, inhibited oxidative stress by activating the Nrf2 pathway in MAFLD (57–59).
In addition to omega-3, oleoylethanolamide supplements exhibited an excellent ability to inhibit oxidative stress in MAFLD progression (60). Giudetti et al. (61) reported that oleoylethanolamide regulated Nrf1 and Nrf2 differently, which increased Nrf1 levels but decreased Nrf2 levels. Reda et al. (62) elaborated that vitamin D3 inhibited oxidative stress in MAFLD by reducing SREBP-1-c expression and increasing PPARα expression to activate the NF-κB signaling pathway.
4 Beverages and snacks are also sources of antioxidants
Green tea is a popular traditional Chinese drink, which rich in catechins, particularly epigallocatechin gallate (EGCG). EGCG has been shown to reduce oxidative stress-induced progression of MAFLD by regulating the Nrf2, AMPK, SIRT1, NF-κB, TLR4/MYD88, TGF-β/SMAD, and PI3K/Akt/FoxO1 signaling pathways (63). Zhou et al. (64) demonstrated that some bioactive flavor compounds present in alcoholic beverages, such as xanthohumol, resveratrol, quercetin, anthocyanins, tetramethylpyrazine, and terpenes, could alleviate oxidative stress. “Baijiu,” the most common spirit in China, is more beneficial than beer and wine in alleviating MAFLD. Since alcohol is a recognized Group 1 carcinogen, we do not recommend consuming alcoholic beverages, especially spirits.
Moreover, Loffredo et al. (65) observed that coca polyphenols suppressed oxidative stress by downregulating NOX2 expression, suggesting that dark chocolate produces antioxidant effects in patients with steatohepatitis. Carminic acid is frequently used as a colorant in beverages and snacks, which could mitigate oxidative stress by blocking the TNF-α pathway and activating the Nrf2 pathway (66).
5 Metal elements bidirectionally regulates oxidative stress
The intake of different metal elements has varying effects on oxidative stress-induced MAFLD progression. On analyzing numerous studies in vivo, Xu et al. (67) discovered that selenium reduced steatosis and fibrosis in MAFLD by alleviating oxidative stress. Zhong et al. (68) reported that excessive copper accumulation induced oxidative stress and lipogenesis, while inhibiting lipolysis. They also elucidated that copper-induced oxidative stress promoted Nrf2 recruitment to the PPARγ promoter and improved lipogenesis, providing evidence for Nrf2 as a potential therapeutic target for MAFLD (68). Iron overload also induced oxidative stress, thereby damaging hepatocytes. Caveolin-1 overexpression augmented the iron storage capacity of hepatocytes by activating the ferritin light chain/ferritin heavy chain pathway in MAFLD and subsequently alleviating excess ferrous ion-induced oxidative stress in the liver (69, 70). Silver nanoparticles significantly elevated oxidative stress levels in mice with MAFLD (71).
6 Discussion
This review highlights studies on food-derived antioxidants and the role of diet in the oxidative stress pathway that contributes MAFLD, with the aim of clarifying the regulatory network involved (Table 1 and Figure 1). Based on the findings, we proposed that a healthy diet can alleviate MAFLD by reducing oxidative stress.
Table 1
Table 1. Food-derived antioxidants, models, exposure and related endogenous molecules.
Figure 1
Figure 1. Regulatory network of food-derived antioxidants in oxidative stress in hepatocytes.
This review primarily includes in vitro and in vivo studies, along with a small number of randomized controlled trials (RCTs). In the in vitro studies included in this review, the cell lines used include human normal liver cell lines (L02, HL-7702), human HCC cell lines (HepG2, Huh-7), mouse normal liver cell line (AML-12), and mouse HCC cell line (Hepa1-6). Included in in vivo experiments primarily used mice and rats as animal models, with oral gavage being the most common administration method, although some studies also employed intraperitoneal injection. The dosage, exposure methods, and exposure duration are presented in Table 1.
Non-enzymatic antioxidants, predominantly found in plant-based foods, are key contributors to oxidative stress mitigation (1). Citrus fruits, for instance, are particularly effective in preventing and managing MAFLD due to their high flavonoids content. Similarly, common fruits like apples, grapes, and, blueberries play a vital role in reducing oxidative stress. Rare fruits, such as açai, are recommended in regions with a high prevalence of MAFLD, given their potent antioxidant properties.
Vegetables, including certain varieties unique in Asia, also demonstrate benefits for MAFLD management, suggesting the value of sharing dietary practices across regions. For example, the Mediterranean diet comprises nutrients and compounds with antioxidant properties, such as polyphenols, carotenoids, fiber, polyunsaturated fatty acids, low-refined foods, and low-sugar foods. In addition, herbal medicine has been identified as a promising therapeutic option for addressing oxidative stress in MAFLD (72–74).
While animal-based foods also contain non-enzymatic antioxidants, excessive consumption, particularly of meat, increases the risk of MAFLD (75). Alternatively, antioxidants derived from animal resources can be provided as supplements. Although certain alcoholic beverages may possess antioxidant properties, their consumption is not recommended for patients with MAFLD due to the potential for liver damage. Selenium, an essential trace element, can be obtained either from selenium-rich foods, such as nuts and game meat, or from carefully selected supplements (76). However, it is critical to avoid excessive intake of mental elements, which may exacerbate MAFLD. Additionally, food contamination remains a significant factor that can amplify the adverse effects of oxidative stress on MAFLD (77).
It is evident that Nrf2 plays a central role in combating oxidative stress in MAFLD. Majority of food-derived antioxidants (e.g., aescin, nobiletin, pterostilbene, hesperetin, and EGCE) can upregulate or activate Nrf2 directly or indirectly. Nrf2 can inhibit oxidative stress by activating multiple regulatory axes and signaling pathways (e.g., MAPK and NF-κB). Therefore, centered on Nrf2, food-derived antioxidants and endogenous molecules form a regulatory network for oxidative stress.
Some of the studies included in this review were conducted in the context of a high-fat diet. Notably, AAE exhibits superior antioxidant capacity in the context of a high-fat diet, suggesting a potential interaction between food-derived antioxidants and dietary composition. This highlights the need for synchronizing antioxidant intake with dietary adjustments. Furthermore, the relationship among diet, oxidative stress, and MAFLD should be explored within a holistic and dynamic framework.
This study has limitations, as it primarily focuses on in vitro and in vivo research, with limited inclusion of RCTs the test these theories in the real world. Moreover, lifestyle modifications, such as physical exercise, play a crucial role in regulating oxidative stress in MAFLD (78, 79). Future research should explore the synergistic effects of diet and lifestyle interventions on oxidative stress, along with the underlying mechanisms. Additionally, more RCTs are needed to validate these findings and provide stronger evidence for clinical application.
Author contributions
ZH: Funding acquisition, Supervision, Writing – original draft, Writing – review & editing. HY: Investigation, Software, Visualization, Writing – original draft, Writing – review & editing. NJ: Investigation, Writing – original draft. LQ: Conceptualization, Project administration, Resources, Supervision, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was funded by National Natural Science Foundation of China (32060289) and Natural Science Foundation of Gansu Province (22JR5RA902).
Acknowledgments
We appreciate Yongning Zhou and Yuping Wang from Lanzhou University very much.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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The authors declare that no Gen AI was used in the creation of this manuscript.
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Keywords: diet, oxidative stress, MAFLD, NAFLD, MASLD
Citation: Hu Z, Yue H, Jiang N and Qiao L (2025) Diet, oxidative stress and MAFLD: a mini review. Front. Nutr. 12:1539578. doi: 10.3389/fnut.2025.1539578
Edited by:
George Grant, Independent Researcher, Aberdeen, United KingdomReviewed by:
Ana J. Fernández-Alvarez, IIBBA-CONICET Leloir Institute Foundation, ArgentinaMuniyappan Madesh, Yangzhou University, China
Rebeca Rosas Campos, Tecnológico de Monterrey, Mexico
Laurence Payrastre, INRAE Occitanie Toulouse, France
Copyright © 2025 Hu, Yue, Jiang and Qiao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Liang Qiao, bGlhbmcucWlhb0BzeWRuZXkuZWR1LmF1
†These authors have contributed equally to this work and share first authorship