JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Zhaolin Sun,Yuhua Wei,Shuangyi Ma,Yuchen Xu,Yuna Zhang,Changxian Li,Jinghan Zhang,Feifei Duan,Jianwei Jiao,Xiuying Duan
Ethnopharmacological relevance Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disease worldwide, primarily caused by poor lifestyle choices and dietary habits. Caulis Bambusae In Taenias , commonly known as Zhuru in Chinese, is a traditional Chinese medicinal material from the Bambusoideae family, frequently used for liver detoxification, liver protection, and lowering lipids. Aim of the study The study aimed to reveal the protective effects and underlying mechanisms of Zhuru extracts (EZR) in treating MASLD. Methods High performance liquid chromatography, liquid chromatography-tandem mass spectrometry, and fourier infrared spectroscopy were used to identify the components of EZR. We utilized oleic acid-treated HepG2/LO2 cells as in vitro models and zebrafish on high-fat diets (HFD) as animal models, and conducted network pharmacology, RNA sequencing, and biological assays, including confocal fluorescence, commercial kits, western blotting, and quantitative PCR, to investigate the lipid-lowering effect of EZR and its underlying mechanisms. Results EZR alleviated lipid accumulation in both in vitro and in vivo models. Analyses through network pharmacology and RNA sequencing revealed that the lipid-lowering properties of EZR were associated with pathways related to lipid biosynthesis, antioxidant functions, and anti-inflammatory mechanisms. Subsequent experimental validation confirmed that EZR decreased the expression levels of FASN, ACC1, HMGCR, ACLY, and LDLR. Additional findings indicated that EZR inhibited mTORC1 activation, leading to the suppression of SREBP1 and SREBP2, thereby mitigating lipid accumulation. Furthermore, EZR was found to downregulate oxidative stress and the levels of inflammatory cytokines. Conclusions EZR demonstrated the ability to lower lipid levels and alleviate HFD-induced MASLD. This is achieved by inhibiting mTORC1/SREBPs-related lipid biosynthesis and reducing oxidative stress and inflammation.
研究领域:
药理学
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肝脏疾病
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Nutrients
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2025
·Vol. 17
·期 15
·2456
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IF 5
Ming Chu,Yingying Tong,Lei Zhang,Yu Zhang,Jun Dang,Gang Li
Background: The metabolic dysfunction-associated steatotic liver disease (MASLD) represents an escalating global health concern, with effective treatments still lacking. Given its complex pathogenesis, multi-targeted strategies are highly desirable. Methods: This study reports the isolation of four flavone C-glycosides (FCGs) from Dianthus superbus L. and explores their potential in treating MASLD. The bioactivity and underlying mechanisms of FCGs were systematically evaluated by integrating network pharmacology, molecular docking, and zebrafish model validation. Results: Network pharmacology analysis revealed that FCGs may modulate multiple MASLD-related pathways, including lipid metabolism, insulin signaling, inflammation, and apoptosis. Molecular docking further confirmed strong binding affinities between FCGs and key protein targets involved in these pathways. In the zebrafish model of MASLD induced by egg yolk powder, FCGs administration markedly attenuated obesity, hepatic lipid accumulation, and liver tissue damage. Furthermore, FCGs improved lipid metabolism and restored locomotor function. Molecular analyses confirmed that FCGs upregulated PPARγ expression to promote lipid metabolism, restored insulin signaling by enhancing INSR, PI3K, and AKT expression, and suppressed inflammation by downregulating TNF, IL-6 and NF-κB. Additionally, FCGs inhibited hepatocyte apoptosis by elevating the BCL-2/BAX ratio. Conclusions: These findings highlight the multi-pathway regulatory effects of FCGs in MASLD, underscoring its potential as a novel therapeutic candidate for further preclinical development.
研究领域:
药理学
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生物化学
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分子生物学
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药用植物研究
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药物开发
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Clinical and Molecular Hepatology
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2024
·Vol. 30
·期 4
·863
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IF 14
Baokai Sun,Xiaoqian Ding,Jie Tan,Jie Zhang,Xueru Chu,Shuimi Zhang,Shousheng Liu,Zhenzhen Zhao,Shiying Xuan,Yongning Xin,Likun Zhuang
Backgrounds/Aims Transmembrane 6 superfamily member 2 (TM6SF2) E167K variant is closely associated with the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the role and mechanism of TM6SF2 E167K variant during MASLD progression are not yet fully understood. Methods The Tm6sf2 167K knock-in (KI) mice were subjected to high-fat diet (HFD). Hepatic lipid levels of Tm6sf2 167K KI mice were detected by lipidomics analysis. Thin-layer chromatography (TLC) was used to measure the newly synthesized triglyceride (TG) and phosphatidylcholine (PC). Results The TM6SF2 E167K variant significantly aggravated hepatic steatosis and injury in HFD-induced mice. Decreased polyunsaturated PC level and increased polyunsaturated TG level were found in liver tissue of HFD-induced Tm6sf2 167K KI mice. Mechanistic studies demonstrated that the TM6SF2 E167K variant increased the interaction between TM6SF2 and PNPLA3, and impaired PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from TG to PC. The TM6SF2 E167K variant increased the level of fatty acid-induced malondialdehyde and reactive oxygen species, and decreased fatty acid-downregulated cell membrane fluidity. Additionally, the TM6SF2 E167K variant decreased the level of hepatic PC containing C18:3, and dietary supplementation of PC containing C18:3 significantly attenuated the TM6SF2 E167K-induced hepatic steatosis and injury in HFD-fed mice. Conclusions The TM6SF2 E167K variant could promote its interaction with PNPLA3 and inhibit PNPLA3-mediated transfer of PUFAs from TG to PC, resulting in the hepatic steatosis and injury during MASLD progression. PC containing C18:3 could act as a potential therapeutic supplement for MASLD patients carrying the TM6SF2 E167K variant.
研究领域:
肝病学
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分子生物学
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代谢
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脂质代谢
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遗传学
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eLife
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2026
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IF 0
Jia He,Ran Li,Cheng Xie,Xiane Zhu,Keqin Wang,Zhao Shan
Metabolic dysfunction-associated steatotic liver disease (MASLD) progression is characterized by hepatic inflammation and cell death, yet the mechanisms underlying Kupffer cell (KC) loss remain poorly understood. Here, we sought to elucidate the metabolic basis of KC death during MASLD. Using metabolomics, immunostaining, and flow cytometry, we evaluated metabolic alterations and KC death throughout early MASLD progression. We found that KC death is an early hallmark of MASLD, exhibiting greater susceptibility and a spatial distribution consistent with KC zonation. Moreoever, KCs undergo progressive metabolic reprogramming toward enhanced glucose utilization during MASLD development, which is correlated with KC death. In combination with biochemical agonist, isotope tracing, and primary KC culture, we further demonstrated that augmented glycolytic metabolism directly drives KC death in vitro. Consistently, using Chi3l1-deficient mice, we further demonstrated that increased glucose utilization accelerates KC death in vivo. Together, these findings establish a causal link between glycolytic activation and KC loss during MASLD progression, highlighting glucose metabolic pathways as potential therapeutic targets to preserve KC homeostasis and mitigate MASLD.
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MOLECULAR AND CELLULAR BIOCHEMISTRY
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2026
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IF 4.7
Du Jiangxia,Shen Minhui,Mu Yuan,Peng Shuoran,Xu Zhifei,Yang Xiaochun,Yang Bo,Luo Peihua,Yan Hao,He Qiaojun
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a prevalent chronic liver disorder with complex pathogenesis and limited therapeutic options. Here, we identify the solute carrier SLC13A3 as a critical regulator of MASLD progression. In a mouse model fed a high-fat, high-cholesterol, and high-fructose (HFHCHF) diet, hepatic SLC13A3 expression was significantly upregulated and positively correlated with disease severity. Liver-specific overexpression of Slc13a3 exacerbated hepatic steatosis, lipid accumulation, and metabolic dysfunction, whereas Slc13a3 knockdown attenuated these pathological phenotypes. Targeted metabolomic analysis revealed that SLC13A3 modulates hepatic NAD + levels, thereby influencing the expression of key lipid metabolism genes, including SREBF1 , CD36 , PPARγ , and SCD1 . These findings highlight a previously unrecognized role of SLC13A3 in MASLD pathogenesis and suggest its potential as a therapeutic target.
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ENVIRONMENTAL HEALTH PERSPECTIVES
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2025
·Vol. 133
·期 5
·057009
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IF 9.8
Shiqi Li,Yun Fan,Min Tang,Xiaorong Wu,Shengjun Bai,Xiancheng Yang,Xueer Zhang,Chuncheng Lu,Chenbo Ji,Paul A Wade,Xu Wang,Wei Gu,Guizhen Du,Yufeng Qin
Background: Bisphenol S (BPS) is a substitute for bisphenol A in various commercial products and is increasingly used globally due to restrictions on bisphenol A usage. Consequently, there are increasing public health concerns that substantial effects mediated by synthetic chemicals may impact human health. Recently, epidemiology studies reported associations between bisphenol exposure and nonalcoholic fatty liver disease [metabolic dysfunction-associated steatotic liver disease (MASLD)]. However, the causal relationship and the molecular mechanisms affecting hepatocellular functions are still unknown. Objectives: Our study aimed to understand the molecular mechanism by which BPS exposure caused hepatic lipid deposition. Methods: C57BL/6J mice were exposed to BPS for 3 months, and its effects were assessed by histology. RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with high-throughout sequencing (ATAC-seq), and cleavage under targets and tagmentation (CUT&Tag) were used to investigate mechanistic details. ATF3 liver-specific knockout mice and cells were used to validate its functions in BPS-induced hepatotoxicity. Results: Here, mice that were chronically exposed to BPS showed significant lipid deposition in the liver and dyslipidemia and were predisposed to MASLD, accompanied with a reprogrammed liver transcriptional network and chromatin accessibility that was enriched for the Atf3 binding motif. Comparing to the control group, we identified numerous differential Atf3 binding sites associated with signaling pathways integral to lipid catabolism and synthesis in the BPS exposure group, resulting in a drastic surge in lipid accumulation. Moreover, knocking out Atf3 in vitro and in vivo significantly attenuates BPS-induced hepatic lipid accumulation via the regulation of chromatin accessibility and gene expression. Besides, inhibiting JunB also eliminates BPS-induced Atf3 upregulation and lipid accumulation. Conclusion: Our study reveals a novel mechanism, through which BPS upregulates JunB and Atf3 to impair hepatic lipid metabolism, and provides new insights into the hepatotoxicity of BPS. https://doi.org/10.1289/EHP17057
研究领域:
毒理学
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环境健康
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分子生物学
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肝脏病学
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表观遗传学
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Frontiers in Pharmacology
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2026
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IF 5.4
Ling Ou,Qian Du,Jiayang Liu,Haiyan Tai,Yinghan Chai,Xiaoqiong Tan,Bing Li,Lirong Tan,Ying Cao,Tingting Zhu
Introduction The liver, as the central metabolic hub of the body, is highly susceptible to diet-induced injury. The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) highlights the urgent need for effective clinical interventions. Currently, there are no specific therapeutics for MASLD, and dietary patterns are closely associated with its pathogenesis, making the exploration of natural bioactive compounds a promising strategy. Methods In this study, we identified acetylshikonin (AS), a component derived from traditional Chinese medicine (TCM), as a core bioactive agent targeting MASLD via a cross-screening strategy of MASLD-related TCM formulas. Male mouse models of MASLD were induced by a high-fat and high-cholesterol (HFHC) diet or carbon tetrachloride (CCl4) and treated with AS (600 mg/kg, gavage) for six consecutive weeks. In vitro experiments were conducted on Hepa1-6 and HCCLM3 hepatocytes stimulated with palmitic acid/oleic acid (PA/OA, 1:2). Integrated network pharmacology, molecular docking, and thermal shift assays were applied to explore the underlying mechanism. Results In vivo results showed that AS markedly attenuated hepatic steatosis (assessed by triglyceride and total cholesterol levels) and liver fibrosis (evaluated by collagen deposition). In vitro, AS suppressed intracellular lipid accumulation (validated by Oil Red O staining and lipid quantification) and inflammatory responses (assessed by pro-inflammatory cytokine expression) in the stimulated hepatocytes. Mechanistically, AS downregulated the transcriptional expression of key genes involved in lipid metabolism (Pparγ and Srebp1c), inflammation (Tnfα and Ccl2), and fibrosis (Col1a1 and Acta2) pathways. Integrated analyses confirmed peroxisome proliferator-activated receptor γ (PPARγ) as the core direct target of AS. Western blotting demonstrated that AS reduced PPARγ protein expression, and its lipid-lowering effect was synergistically enhanced when combined with the PPARγ antagonist GW9662. Discussion This is the first study to definitively confirm that AS exerts therapeutic effects on diet-induced MASLD by targeting the PPARγ signaling pathway, thereby reducing hepatic lipid deposition, alleviating inflammation, and ameliorating liver fibrosis progression. Our findings provide novel experimental evidence supporting the use of natural products in MASLD treatment and lay a theoretical foundation for the application of AS in the health management of diet-related liver diseases.
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Cell Reports
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2026
·Vol. 45
·期 2
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IF 6.9
Chenyi Xie,Xiaofang Cui,Wei Wei,Peicheng Hong,Lujia You,Ziyao Chen,Lin Li,Lan Wang,Na Wang,Ze-Guang Han
Metabolic dysregulation has been recognized as a crucial driver of tumorigenesis, particularly in metabolic dysfunction-associated steatotic liver disease (MASLD)-related hepatocellular carcinoma (HCC). However, the underlying mechanisms remain poorly understood. Here, we identify lysosome-localized insulin receptor tyrosine kinase substrate (IRTKS) as a key activator of the metabolic master regulator mTORC1 through phospho-antibody array screening. IRTKS forms membrane-associated condensates that selectively interact with the GTPase RRAGD, a key upstream regulator of mTORC1, thereby enhancing the sensitivity of mTORC1 to free amino acids. Notably, in hepatic knockin mice, Irtks-mediated mTORC1 hyperactivation promotes obesity, hepatic lipid accumulation, and the progression from MASLD to metabolic dysfunction-associated steatohepatitis and HCC. Conversely, pharmacological inhibition of mTORC1 or genetic ablation of Irtks ameliorates hepatic steatosis, inflammation, and metabolic dysfunction in mouse models. Our study establishes IRTKS as a central regulator of mTORC1-dependent metabolic reprogramming during hepatocarcinogenesis, providing potential therapeutic targets for MASLD-associated liver cancer.
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npj Science of Food
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2026
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IF 9.7
Wang Xiaoran,Song Yagang,Zhao Wenyu,Liu Yuting,Fu Yiping,Zhang Yu,Zhao Quanyou,Miao Mingsan,Zhao Wenxia,Wang Xianbo,Li Zhanzhan
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health burden with limited therapeutic options. Cinnamomum cassia , a medicinal-food homologous plant, contains principal bioactive cinnamaldehyde (CA), whose anti-MASLD mechanisms require clarification. This study employed both a high-fat diet (HFD)-induced MASLD model and a free fatty acid (FFA)-stimulated cell model. CA administration attenuated intracellular lipid accumulation in vitro and ameliorated both hepatic steatosis and systemic hyperlipidemia in vivo, while inhibiting hepatic lipid peroxidation. Mechanistically, integrated RNA-seq, network pharmacology, siRNA, immunofluorescence, and transmission electron microscopy analyses identified the SIRT1/FOXO1–autophagy axis as CA’s key regulatory pathway. Gut microbiome profiling revealed CA’s capacity to ameliorate HFD-induced dysbiosis, particularly enriching Lachnospiraceae_NK4A136 . Fecal microbiota transplantation (FMT) and Spearman correlations link serum lipids and hepatic injury factors to gut microbiota, indicating partially microbiota-mediated metabolic modulation by CA. Collectively, CA ameliorates MASLD through coordinated autophagy enhancement and microbial homeostasis restoration, holding promise as a functional food ingredient for metabolic liver disease prevention.
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Nature Communications
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2026
·Vol. 17
·期 1
·2821
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IF 18.1
Xiao Hai-Tao,Song Peng,Jin Jing,Wang Yong-Dan,Xu Yin-Yue,Wu He,Shao Xue-Xue,Gan Qi-Feng,He Jian,Wen Yan-Rong,Zhu Jing,Chen Bao-Yi,Zhou Ping,Lai Li-Na,Yang Hua,Li Ping,Zheng Zu-Guo
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern that affects nearly one-quarter of the world’s population. General control non-repressed protein 5 (GCN5), a histone acetyltransferase (HAT), has been implicated in the progression of several diseases, but its role in MASLD remains unclear. Here, we provide the experimental evidence that progressive human and male murine MASLD is driven by GCN5, but not by p300/CREB binding protein associated factor (PCAF) activation. Hepatocyte-specific GCN5 overexpression accelerates MASLD progression, whereas its ablation alleviates disease severity. Moreover, pharmacological inhibition of GCN5 with CPTH2 protects against MASLD. Metabolomics and RNA-seq analyses demonstrate that GCN5 promotes de novo lipogenesis (DNL) by upregulating SREBP1c-mediated transcription of lipogenic genes. Mechanistically, GCN5 acetylates histone H3 at the SREBP1c promoter, enhancing transcription through its intrinsic acetyltransferase activity. Our findings further identify GCN5 as a key regulator of LXRα-induced SREBP1c expression, suggesting that targeting GCN5 may selectively inhibit SREBP1c-driven DNL without impairing LXRα-mediated reverse cholesterol transport (RCT). Notably, combined treatment with the Liver X Receptor (LXR) agonist T0901317 and CPTH2 synergistically reduced lipid accumulation in vitro and in vivo, highlighting a promising therapeutic strategy for MASLD.
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EXPERIMENTAL AND MOLECULAR MEDICINE
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2026
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IF 17.5
Gao Jun,Yang Meng,Duan Rui,Huang Tongling,Li Pengda,Gao Lu,Lu Zhaocheng,Wong Chi-Wai,Geng Chang-An,Guan Min
Lactate has been recognized as a major fuel substrate and also a lactyl-group donor for histone lysine lactylation. Hepatocytes act as lactate-consuming cells owing the high oxidative capability especially during exercise, a primary nonpharmacological intervention for alleviating metabolic dysfunction-associated steatotic liver diseases including steatohepatitis (MASLD/MASH). However, little is known regarding how lactate links the metabolic–epigenetic axis in hepatocytes. Here we show that declined estrogen-related receptor α (ESRRA) expression occur in MASLD/MASH accompanied with elevated levels of lactate and histone lactylation, particularly H3K18la. Such dysregulation can be partially rescued by chronic exercise in aged mice or exacerbated by genetic ablation of hepatocyte ESRRA. Mechanistically, exercise-induced ESRRA/PPARGC1A facilitates lactate consumption through transcriptional regulation of lactate dehydrogenase B and glucose-6-phosphatase catalytic subunit 1, rewiring lactate from a lactyl donor to gluconeogenic precursor in hepatocytes. Hepatocyte-specific ESRRA overexpression counteracts MASLD/MASH progression in mice, rectifying aberrant H3K18la accumulation and its marked gene transcripts that are involved in liver pathology. Our findings reveal that ESRRA functions as an exercise executor linking metabolism with epigenetic modification, highlighting a gluconeogenic–epigenetic regulatory axis that could be fine-tuned to mitigate risk factors of MASLD/MASH such as aging, menopause, a sedentary lifestyle and malnutrition. The alternative text for this image may have been generated using AI.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Yong Li,Ze-Jie Zeng,Anqi Ye,Weizhi Wang,Danxia Huang,Lijun Hu,Shan Li,Jing Li,Lei Zhang
Ursocholic acid (UCA) alleviates experimental metabolic dysfunction-associated steatotic liver disease (MASLD) by reducing hepatic lipid accumulation in vitro and in vivo. • UCA is a natural AMPK agonist that inhibits key lipogenic genes, ameliorating hepatic lipid metabolism imbalances. • UCA exhibits dose-proportional pharmacokinetics and preferential hepatic distribution, with a half-life comparable to UDCA. • Preferential hepatic distribution and direct AMPK binding may concentrate pharmacological effects in the liver, potentially reducing systemic off-target risks. Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health challenge lacking effective therapeutic agents. Ursocholic acid (UCA), a natural bile acid with established cholesterol-lowering properties, has not been evaluated for MASLD treatment. Objective To investigate the therapeutic efficacy, mechanism of action, and pharmacokinetic profile of UCA in MASLD. Methods Hepatoprotective effects were assessed in free fatty acid (FFA)-induced Huh7 cells and high-fat diet (HFD)-fed mice. RNA sequencing identified target pathways. Direct AMPK interaction was validated by molecular docking, molecular dynamics simulation, and cellular thermal shift assay. Pharmacokinetics were compared with ursodeoxycholic acid (UDCA). Results UCA dose-dependently reduced hepatic lipid accumulation in vitro and in vivo . Transcriptomic analysis revealed AMPK signaling as the primary modulated pathway. Mechanistically, UCA directly bound to AMPK, promoted Thr172 phosphorylation, and downregulated lipogenic genes ( SREBF1 , LPIN1 , FASN , SCD1 ), and these effects were abrogated by Compound C (AMPK inhibitor). Pharmacokinetically, UCA exhibited dose-proportional oral exposure (AUC last 1,120–13,700 h·ng/mL across 30–300 mg/kg) with a terminal half-life of 3.7–5.9 hours, comparable to UDCA. Conclusion UCA is a direct AMPK agonist that ameliorates MASLD by suppressing the SREBF1/LPIN1 lipogenic axis, representing a promising natural therapeutic candidate. Download: Download high-res image (118KB) Download: Download full-size image
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