Journal of Advanced Research
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2025
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IF 13
Jia Xu,Bingxin Huangfu,Teng Wang,Xinxin Ren,Feng Zhang,Kunlun Huang,Xiaoyun He
Introduction The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rising, while current pharmacological treatments are often limited by adverse effects. Artemether (Art), a derivative of artemisinin, has demonstrated therapeutic potential against MAFLD, but its direct molecular targets remain unclear. Objectives This work focuses on Art’s therapeutic effects and molecular targets in MAFLD. Methods In this study, MAFLD was induced in C57BL/6J male mice via high-fat diets, followed by treatment with Art at 10 or 50 mg/kg·bw/d; obeticholic acid served as a positive control. Glucose tolerance, serum biochemistry, and liver histology were assessed. Fatty acid-induced MAFLD models in HepG2 and primary mouse hepatocytes were treated with Art (5 µM or 25 µM), and lipid accumulation was evaluated. Protein target identification involved drug affinity responsive target stability (DARTS), cellular thermal shift assay (CESTA), chemical proteomics, and molecular docking etc. Heat shock protein 90 (HSP90) and epidermal growth factor receptor (EGFR) were confirmed as direct targets of Art through over-expression, inhibition, and knockdown techniques in cells and mice. Results Art dose-dependently reduced hepatic lipid accumulation in MAFLD mice and suppressed oleic-palmitic acid–induced lipid droplet formation in vitro . HSP90 and EGFR were identified as direct binding targets of Art, which disrupted the HSP90–EGFR complex, reducing EGFR stability and expression. The therapeutic efficacy of Art was not further enhanced when administered following HSP90 or EGFR knockdown, confirming that HSP90 and EGFR function as key molecular targets of Art. Conclusion These findings identify EGFR as a key target of Art, modulated directly or via HSP90, thereby offering new insights into Art’s multi-target therapeutic mechanism in MAFLD.
研究领域:
药理学
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分子生物学
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肝病学
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生物化学
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药物研发
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Scientific Reports
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2025
·Vol. 15
·期 1
·1-23
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IF 3.9
Sun Yuan-dong,Zhang Hao,Gong Xiao-long,Li Yuan-min,Han Ruiqin,Zhou Chun-xiao,Han Jian-jun
Metabolic Associated Fatty Liver Disease (MAFLD), previously known as Non-Alcoholic Fatty Liver Disease, is a growing global health issue associated with obesity, type 2 diabetes, and metabolic syndrome. This study investigates the potential of metformin, a common anti-diabetic drug, to slow the progression of MAFLD using a multi-omics approach. Male Wistar rats were fed a choline-deficient diet to induce MAFLD and treated with metformin through their drinking water for 48 weeks. We conducted a comprehensive analysis including liver histology, untargeted metabolomics, lipidomics, and gut microbiome profiling to assess the effects of metformin on liver and gut metabolic patterns. Metformin administration led to significant changes in gut microbiome diversity and the abundance of specific microbial species in MAFLD rats. Histological analysis showed that metformin-treated rats had reduced lipid accumulation and fibrosis in the liver compared to untreated MAFLD rats. Metabolomic and lipidomic analyses revealed that metformin corrected abnormal lipid metabolism patterns, reduced hepatic fat deposition, and influenced key metabolic pathways associated with MAFLD progression. Our findings suggest that metformin has a protective role against MAFLD by modulating gut microbiota and liver metabolism, thereby slowing the progression of hepatic fibrosis. This study provides insights into the therapeutic potential of metformin for MAFLD by addressing metabolic pattern disorders and abnormal changes in gut microbial diversity, highlighting its impact on lipid metabolism and gut-liver axis interactions.
研究领域:
生物医学
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微生物组学
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代谢组学
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病理学
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JOURNAL OF GASTROENTEROLOGY
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2025
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IF 5.5
Ren Bingyu,Li Han,Liu Shenglu,Huang Zhiwei,Bai Junjie,Jiang Zhonghao,Xu Tongjie,Gu Boyuan,Yu Wenhao,Sun Lei,Tan Peng,Fu Wenguang
Background and Aims Inflammatory cell infiltration in the liver is a hallmark of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the pathological events that trigger the infiltration of inflammatory cells to mediate MAFLD pathogenesis remains poorly understood. This study aims to investigate the function and mechanism of Hic-5 on hepatic inflammation of MAFLD. Methods MAFLD animal models were fed a methionine- and choline-deficient (MCD) diet in Hic-5 knockout mice. Liver tissues were analyzed by immunohistochemical staining, immunofluorescence and flow cytometry, with a particular focus on the impact on the immune microenvironment. Results Hic-5 deficiency alleviates the severity of MAFLD, particularly the inflammation response. Gain- and loss-of-function experiments revealed that Hic-5 deficiency results in decreased neutrophil proliferation and increased apoptosis, as well as impaired migration. Conversely, Hic-5 overexpression had the opposite effects. This study confirmed that METTL3-mediated methylation of m 6 A stabilizes Hic-5 mRNA and promotes its expression, which in turn regulates the infiltration of neutrophils by the CXCL1-CXCR2 axis. Conclusions The study reveals the role of Hic-5 in regulating neutrophils and indicates that it may be a potential therapeutic target for MAFLD.
研究领域:
肝病学
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免疫学
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分子生物学
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病理学
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Cell Communication and Signaling
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2026
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IF 11.6
Deng Weiqian,Yang Xiaoting,Wu Hao,Tang Haojun,Wang Xiaodan,Tu Shuangxi,Yin Kai,Zhu Xiao
Metabolic-associated fatty liver disease (MAFLD), the most prevalent chronic hepatic disorder globally, is pathologically characterized by excessive intrahepatic lipid deposition, oxidative stress, and chronic low-grade inflammation. Apolipoprotein A-I binding protein (AIBP), a critical modulator of lipid metabolism, cellular signaling pathways, inflammatory responses, and metabolic homeostasis, has not been thoroughly investigated in the context of MAFLD pathogenesis. In this study, we identified a significant downregulation of AIBP expression in both high-fat diet (HFD)-induced MAFLD murine models and palmitic acid (PA)-treated HepG2 cells. Systemic AIBP deficiency exacerbated metabolic dysregulation and induced profound perturbations in hepatic architecture and function, culminating in aggravated liver injury. This was evidenced by enhanced steatosis, elevated pro-inflammatory cytokine production, and increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Transcriptomic profiling and molecular characterization of AIBP-deficient HepG2 cells corroborated these pathological alterations. Mechanistic investigations revealed that AIBP silencing potentiates hepatic damage through integrin β3 (ITGβ3)-mediated hyperactivation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling cascade. Notably, hepatocyte-specific AIBP overexpression effectively ameliorated these metabolic and inflammatory aberrations. Collectively, our findings establish AIBP as a pivotal hepatoprotective regulator in MAFLD pathogenesis and propose a novel therapeutic paradigm for MAFLD and associated metabolic disorders through targeted AIBP modulation. This study provides compelling evidence for the development of AIBP-centered therapeutic strategies to mitigate MAFLD progression.
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PHYTOMEDICINE
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2026
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IF 11.3
Jiahao Wang,Lei Peng,Haoran Sun,Jie Zeng,Rui Fu,Haonan Zhang,Rong Liang,Yan Lin,Jiazhou Ye,Liang Ma,Xiaoling Luo,Heng Jiang,Guobin Wu,Bo Qian,Rongyun Mai
Background Semen Persicae , a traditional Chinese medicine, has shown potential in alleviating metabolic dysfunction-associated fatty liver disease (MAFLD). However, the complexity of components limits its clinical application. Purpose To identify the key active component of Semen Persicae responsible for attenuating MAFLD and to elucidate the underlying mechanism. Methods The chemical components of Semen Persicae were characterized using mass spectrometry. A high-fat diet-induced MAFLD mouse model and primary liver sinusoidal endothelial cells (LSECs) were employed. Liver histopathology was used to evaluate the efficacy and safety of amygdalin (Amy). Single-cell RNA sequencing (scRNA-seq) and untargeted metabolomics analyses of mouse livers were integrated to preliminarily investigate the mechanism. Scanning electron microscopy (SEM) and assessment of fenestration markers were used to evaluate the fenestrae status of LSECs. Cytoplasmic calcium ion (Ca2+) staining, along with measurements of prostaglandin E2 (PGE2) and inositol triphosphate (IP3) levels, was applied to assess Ca2+ overload in LSECs. Results Mass spectrometry identified Amy as a major component of Semen Persicae. In a diet-induced MAFLD mouse model, Amy treatment dose-dependently attenuated disease progression, showing therapeutic efficacy comparable to liraglutide, with marked improvements in systemic metabolic parameters and significant reductions in hepatic steatosis and inflammation. Single-cell RNA sequencing identified liver sinusoidal endothelial cells (LSECs) as the most responsive cell population, with Amy markedly reducing the abundance of capillarized LSEC states. Ultrastructural analyses further demonstrated that the reduced fenestration density observed in MAFLD was substantially restored following Amy treatment. Integrated transcriptomic and metabolomic analyses revealed that arachidonic acid metabolism and endoplasmic reticulum Ca²⁺ signaling were prominently affected by Amy. In vitro experiments further confirmed that Amy reduced elevated PGE2 and IP3 levels, thereby suppressing excessive endoplasmic reticulum Ca²⁺ release. Conclusion Amy effectively ameliorates LSECs defenestration by reversing IP3-induced cytoplasmic Ca2+ overload, highlighting its potential as a plant-derived therapeutic candidate for MAFLD.
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FASEB JOURNAL
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2025
·Vol. 40
·期 1
·e71393
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IF 4.2
Ying Wang,Jia Luo,Weiqi Zhang,Yu Ban,Yuyou Zhang,Pengyao Lin,Rong Fang,Zhaoxia Xia,Lihui Du,Aiming Liu
Biological rhythm output by central and peripheral circadian clock is closely associated with metabolic dysfunction-associated fatty liver disease (MAFLD) development, but the down-stream targets of the hepatic clock are not well known. This work aimed to investigate how hepatic circadian clock regulates MAFLD development. Male mice were fed a 45% high fat diet (HFD) for 8 weeks to screen the lipid metabolism genes regulated by clock factors in natural MAFLD development. Core circadian factor circadian locomotor output cycles kaput (CLOCK) knockdown and over-expression in cellular models were performed to explore the role of its potential target SREBP1 found in vivo. rAAV8-CAG-EGFP- Clock was delivered in mice to validate the role of SREBP1 signaling regulated by CLOCK. HFD induced body weight gain and steatosis in the liver. The hepatic core circadian factor CLOCK was significantly down-regulated and the lipid metabolism was disrupted including up-regulation of Srebf1 which encodes transcription factor SREBP1. In mouse and human cellular models, SREBP1 and the lipid accumulation were increased by CLOCK knockdown and decreased by CLOCK over-expression. When CLOCK was over-expressed in vivo, liver triglyceride and total cholesterol were reversed and hepatic steatosis was attenuated where the transcription factor SREBP1 signaling was down-regulated. In conclusion, SREBP1 signaling is a down-stream target of CLOCK deeply involved in regulating the natural MAFLD development. Graphical In natural development of high-fat diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD), dysregulation of lipid metabolism genes by SREBP1 was driven by down-regulation of hepatic circadian locomotor output cycles kaput (CLOCK). In vivo and in vitro manipulation of hepatic CLOCK negatively regulated SREBP1 and reversed the lipid storage in mouse and human models. Thus, SREBP1 acts as a downstream target of the hepatic CLOCK, which mediates the exacerbation of MAFLD development.
研究领域:
分子生物学
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内分泌与代谢
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时间生物学
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肝病学
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营养科学
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Chinese Medicine
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2026
·Vol. 21
·期 1
·34
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IF 5.7
Fan Haibo,Hou Yalei,Li Yue,Zheng Zhiwen,Wang Xuelun,Li Yunfeng,Li Yongmin
Background Metabolic-associated fatty liver disease (MAFLD) is a common metabolic disease with complex pathogenesis and lack of effective treatment. Si-Ni-San (SNS), a traditional Chinese medicine, has emerged as a promising candidate for MAFLD treatment. However, the protective mechanism remains unclear. Methods C57BL/6N mice were fed with high-fat diet (HFD) for 12 weeks to establish MAFLD mouse model. Concurrently, oleic acid-induced HepG2 cells were used in vitro as a cellular model for MAFLD. The effects of SNS and the positive drug obeticholic acid on hepatic lipid droplets deposition in MAFLD mice and cell models were evaluated. The expression levels of farnesoid X receptor (FXR) and glycerol 3-phosphate acyltransferase 4 (GPAT4) were detected by western blot. The siRNA and dual-luciferase reporter assay were used to detect the interaction between FXR and GPAT4. High-performance liquid chromatography (HPLC) was used to identify the active components in the SNS aqueous solution, and their binding affinities to targets were detected through molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR). Results The active ingredients of SNS were identified by HPLC. SNS ameliorated hepatic lipid droplets deposition in both mouse and cellular models of MAFLD. SNS up-regulated the expression of FXR and down-regulated the expression of GPAT4 in hepatic tissues, thereby modulating proteins involved in hepatic lipolysis and lipophagy. FXR reduced lipid droplets accumulation by inhibiting GPAT4. The dual-luciferase reporter assay confirmed that FXR transcriptionally regulated and inhibited GPAT4 expression. Furthermore, molecular docking and molecular dynamics simulations predicted potential interactions between the active components of SNS and the FXR and GPAT4 proteins, with the binding affinity for FXR being subsequently confirmed through SPR analysis. Conclusion This study provided a new mechanistic exploration for FXR in improving MAFLD and broadened the research direction on the mechanisms by which SNS reduced hepatic lipid droplets deposition. It also offers a molecular dynamics basis for subsequent studies on how active components in SNS exert their effects through binding to FXR.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 4.7
Tianxiao Hu,Jiayu Qi,Yinuo Xu,Jia He,Qingying Tan,Jie Hao,Jing Wang,Jiewei Hong,Jianwei Wang,Lin Chen,Xiaobing Dou
This study aims to investigate the molecular mechanisms by which 4-hydroxynonenal (4-HNE) regulates hydrogen sulfide (H₂S)-producing enzymes, mediating the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) during pregnancy, thereby offering novel molecular targets for early diagnosis and intervention of related disorders. By establishing a MAFLD pregnant mouse model, we comprehensively examined the regulatory effects of 4-HNE on placental function and its interaction with the H₂S system. We found that MAFLD pregnant mice exhibited significant glucose metabolic disorders, hepatic steatosis, and placental damage. Mechanistically, 4-HNE disrupts H₂S biosynthesis, thereby impairing its inhibitory effect on the inflammasome pathway while simultaneously activating inflammatory cascades. This synergistic action exacerbates placental pathological damage, manifesting as abnormal vascular function and impaired materno-fetal exchange. Notably, exogenous H₂S intervention partially reversed 4-HNE-induced toxicity, suggesting the therapeutic potential of targeting this pathway. These findings demonstrate the pivotal role of the “4-HNE–H₂S–NLRP3” regulatory axis in MAFLD-associated placental injury, providing novel mechanistic insights and potential therapeutic targets for pregnancy complications.
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CHEMISTRY & BIODIVERSITY
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2026
·Vol. 23
·期 5
·e03580
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IF 2.9
Wen-Xuan Zhao,Rui Zhang,Guo-Qiang Li,Cun-Ping Wang,Yan-Feng He,Hong-Tao Bi
Trigonella foenum-graecum L. seed polysaccharides (FSP) belong to a very important species of biological macromolecules with prebiotic activity, which are the basic substances that have broad application potential in food and pharmaceutical fields. However, systematic studies focusing on the compound enzyme-assisted extraction of FSP and their hepatoprotective effects remain limited. This study aimed to optimize the compound enzyme-assisted extraction of FSP, analyze the structural features of deproteinized FSP (DFSP), and evaluate its therapeutic potential against metabolism-associated fatty liver disease (MAFLD). The results showed that the optimal extraction conditions were an enzymatic hydrolysis temperature of 50°C, an enzymatic hydrolysis pH of 5.3, an enzymatic hydrolysis time of 1.9 h, and a liquid-to-solid ratio of 23:1 mL g −1 , under which the polysaccharide yield reached 24.88% ± 0.15%. The molecular weight distribution of fenugreek seed polysaccharides was 7157.46, 2785.65, and 642.61 Da, and they were mainly composed of mannose and galactose. In vivo experiments indicated that DFSP exerted a liver-protective effect on MAFLD mice, accompanied by improvements in lipid metabolic parameters, antioxidant capacity, and inflammatory responses. Therefore, this study provides a scientific basis for further investigations into the fine structure and potential hepatoprotective effects of DFSP. Graphical
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FREE RADICAL BIOLOGY AND MEDICINE
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2022
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IF 8.101
Shuhui Liu,Zhangshan Gao,Wanqiu He,Yuting Wu,Jiwen Liu,Shuo Zhang,Liping Yan,Shengyong Mao,Xizhi Shi,Wentao Fan,Suquan Song
Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disorders in the world, and yet has no approved pharmacotherapy due to the etiology is complex. In the last ten years, increasing evidence have identified the environmental pollutants as risk factors for MAFLD. However, the underlying mechanism remains unclear. Our study found that bromoacetic acid (BAA, a typical kind of environmental toxin) increased triglycerides and total cholesterol levels as well as induced obvious hepatic steatosis and inflammation. The lipidomics showed that ferroptosis was implicated in the environmental toxin–linked MAFLD. Besides, the analysis of microbial metabolomics showed significant change of gut microbiome in BAA groups and the content of gut microbiota metabolite (glycochenodeoxycholate, GCDCA) increased sharply. In vitro study, we observed features of ferroptotic cells by transmission electron microscopy after BAA/GCDCA treatment . Besides, we demonstrated that BAA/GCDCA significantly increased iron contents, with upregulating transferrin receptor (TFR) and acyl-CoA synthetase long-chain family 4 (ACSL4) expression levels. By contrast, iron chelator or silencing TFR relieved BAA/GCDCA-induced lipid metabolism disorder and inflammation. What's more, the interaction between TFR and ACSL4 was also identified. Taken together, we found that, in response to environmental toxin , gut microbiota metabolite GCDCA activates TFR-ACSL4-mediated ferroptosis, which triggered subsequent lipid metabolism disorder and inflammation. Moreover, these findings firstly highlighted the functional relevance among ferroptosis, lipid metabolism and gut microbiota metabolite during environmental pollutant exposure, which shed light on the deep mechanism of environmental toxin-related MAFLD, providing potential targets for the prevention of MAFLD.
研究领域:
肝病学
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毒理学
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微生物学
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代谢组学
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脂质组学
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Jirui Wei,Xiaozheng He,Tingting Shi,Xiayu Jin,Jun Huang,Qingyao Du,Junda Huang,Tao Li,Xunjie Xie,Yuxin Huang,Chengtao Nie,Yiqi Fan,Xixiao Yang,Luyao Song,Waijiao Tang
Epidemiological studies indicate that Metabolic Associated Fatty Liver Disease (MAFLD) has become the most prevalent chronic liver disease globally. Identifying bioactive molecules from natural plants that can prevent and ameliorate MAFLD is an effective approach to discovering new MAFLD therapeutics. Liupao tea possesses antioxidant and metabolic regulatory properties. This study aimed to identify the active components of Liupao tea polyphenol extract (PLE), and its potential targets and mechanisms of action in the prevention of MAFLD. We performed experiments on MAFLD mice to establish the prevention efficacy of PLE against MAFLD and determine its optimal dosage. Furthermore, network pharmacology, molecular docking, and SPR were performed to predict that PLE’s targets for preventing MAFLD concentrate on the hepatic EGFR target. Knockout of EGFR in hepatocytes attenuated the effects of PLE. These findings indicate that PLE inhibits lipid accumulation by downregulating the EGFR/pEGFR-AKT/pAKT-SREBP-1-ACC1 pathway through binding to the EGFR receptor, thereby preventing MAFLD.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2026
·Vol. 27
·期 10
·4411
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IF 5.6
Rui Mao,Yuxia Guo,Haiyan Zhang,Ruiqi Wang,Yangang Cheng,Huifeng Li,Yan Wang,Yingli Wang
Emodin exhibits promising hepatomodulatory potential, yet its precise actions remain poorly characterized across distinct hepatic pathological states. Dose-dependent effects of emodin (40, 80, and 120 mg/kg) were investigated in mice with metabolic dysfunction-associated steatotic liver disease (MASLD), as well as healthy control mice, through integrated histopathological, biochemical, metabolomic, and gut microbiota profiling. The 80 mg/kg dose tended to yield the most favorable hepatoprotective outcomes in MASLD mice, whereas the 120 mg/kg dose was accompanied by apparent adverse hepatic alterations in normal mice. Correlative analyses further suggested that such divergent hepatic responses may be potentially linked to the gut microbiota–short-chain fatty acid (SCFA) axis, as well as the modulation of BAX/Bcl-2 balance and ESR1 expression. The hepatic effects of emodin are state- and dose-dependent. The dose of 80 mg/kg may represent a plausible candidate therapeutic range for MASLD, and the gut–liver axis is proposed as a likely underlying regulatory pathway.
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