Chinese Medicine
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2026
·Vol. 21
·期 1
·223
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IF 7.4
Liang Hui-Mei,Xu Yin-Yue,Miao Kun,Xiao Hai-Tao,Wang Yong-Dan,Jin Jing,Wu He,Chen Bao-Yi,Xu Li-Jun,Zhu Jiang-Ping,Lai Li-Na,Zheng Zu-Guo
Background Astragaloside IV (AS-IV), a bioactive saponin from Astragalus membranaceus, shows promise for treating metabolic dysfunction-associated steatotic liver disease (MASLD), though its mechanisms remain unclear. Purpose This study aimed to elucidate how AS-IV alleviates hepatic steatosis, specifically investigating its epigenetic regulation of lipogenesis. Methods Using high-fat diet-fed mice and lipids-loaded hepatocytes, we assessed AS-IV's effects through SREBP-1c overexpression, histone acetylation analysis, and GCN5 rescue experiments. Results AS-IV significantly reduced hepatic steatosis by suppressing SREBP-1c-mediated de novo lipogenesis. Mechanistically, it inhibited histone acetyltransferase GCN5, decreasing H3K9/H3K14 acetylation at the SREBP-1c promoter and attenuating LXRα-driven transcription. GCN5 overexpression reversed AS-IV's suppression of SREBP-1c and lipid accumulation. Conclusion AS-IV uniquely downregulates GCN5 expression at the transcriptional level, exerting epigenetic regulation to disrupts lipogenic programming, This represents a novel multi-target approach against MASLD that connects natural product pharmacology with epigenetic modulation.
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Journal of Pharmaceutical Analysis
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2025
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IF 8.9
Yuxuan Chen,Chendong Liu,Qian Yang,Jingtao Yang,He Zhang,Yong Zhang,Yanruyu Feng,Jiaqi Liu,Lian Li,Dapeng Li
Liraglutide (Lira), a glucagon-like peptide-1 (GLP-1) receptor agonist approved for diabetes and obesity, has shown significant potential in treating metabolic dysfunction-associated steatotic liver disease (MASLD). However, its systematic molecular regulation and mechanisms remain underexplored. In this study, a mouse model of MASLD was developed using a high-fat diet (HFD), followed by Lira administration. Proteomics and glycoproteomics were analyzed using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS), while potential molecular target analysis was conducted via quantitative real-time polymerase chain reaction (qPCR) and Western blotting. Our results revealed that Lira treatment significantly reduced liver weight and serum markers, including alanine aminotransferase (ALT) and others, with glycosylation changes playing a more significant role than overall protein expression. The glycoproteome identified 255 independent glycosylation sites, emphasizing the impact of Lira on amino acid and carbohydrate metabolism, and ferroptosis. Simultaneously, proteomic analysis highlighted its effects on lipid metabolism and fibrosis pathways. 21 signature molecules, including 7 proteins and 14 N -glycosylation sites, were identified as potential targets. A Lira hydrogel formulation (Lira@fibrin (Fib) Gel) was developed to extend drug dosing intervals, offering enhanced therapeutic efficacy in managing chronic metabolic diseases. Our study demonstrated the importance of glycosylation regulation in the therapeutic effects of Lira on MASLD, identifying potential molecular targets and advancing its clinical application for MASLD treatment.
研究领域:
分子生物学
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代谢组学
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肝脏疾病研究
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Journal of the Endocrine Society
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2025
·Vol. 10
·期 3
·
IF 3.1
de Crecy Chloe A,Yang Qiang,Liu Mei,Yin Rui,Sharma Anu
ContextRegardless of age, metabolic dysfunction-associated steatotic liver disease (MASLD) occurs in 70% of adults with type 2 diabetes (T2D) and increases the risk of metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and cirrhosis. However, many studies focus on older adults.ObjectiveTo determine the frequency of screening for MASLD in young adults with T2D attending outpatient clinics.MethodsA retrospective cohort study on young adults (aged 18-44 years) with T2D who accessed care at a tertiary care center from January 1, 2018, to December 31, 2022. At-risk MASH was diagnosed with vibration-controlled transient elastography, magnetic resonance elastography, or liver biopsy.ResultsOf 6891 participants included, 16% (n = 1100) had a diagnosis of MASLD. Those with MASLD were more likely to have cardiometabolic risk factors (83% vs 72%, P < .001) and cardiovascular disease (22% vs 16%, P < .001). Only 12% of those with MASLD underwent further investigation (1.9% of the total cohort), which was associated with dyslipidemia (odds ratio [OR], 2.4; 95% CI, 1.5-3.8), ALT >40 U/L (OR, 2.1; 95% CI, 1.4-3.0), or the use of 3 or more diabetes medications (OR, 2.1; 95% CI, 1.5-3.1). In those with further workup, 38% had at-risk MASH. The fibrosis-4 index was elevated in 16% of those with MASLD and only 28% of those with confirmed at-risk MASH or worse.ConclusionScreening for MASLD in young adults with T2D is frequently missed. There is a lack of accurate noninvasive tools in this population. Increased awareness of screening young adults with T2D for at-risk MASH is urgently needed to prevent progression to cirrhosis.
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LIFE SCIENCES
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2026
·
IF 6.4
Jun Zhou,Haojie Jin,Yifan Zheng,Kunying Ding,Yu Long,Chenjie Yu,Yueran Zhang,Fen Zhuge,Minhua Chen,Zhengwei Fu,Yinhua Ni
Cyclo(Val-Pro) and cyclo(Phe-Phe) ameliorate metabolic disorders and inflammation. • Cyclo(Val-Pro) and cyclo(Phe-Phe) target chemokine signaling in the liver. • Cyclo(Val-Pro) and cyclo(Phe-Phe) regulate macrophage infiltration/polarization. • Cyclo(Val-Pro) targets CCR2 and cyclo(Phe-Phe) targets ADCY7 in macrophages. Metabolic dysfunction-associated steatotic liver disease (MASLD), hallmarked by hepatic metabolic disorders and chronic inflammation, is a growing global public health threat with limited approved pharmacological options. Natural cyclodipeptides exhibit favorable metabolic stability and bioactivity profiles, making them ideal molecules for drug discovery in metabolic diseases; however, their roles and mechanisms in MASLD remain poorly defined. Here, we investigated the protective effects of cyclo(Val-Pro) and cyclo(Phe-Phe), two bioactive cyclodipeptides previously identified in hydrolyzed chicken meat extract (HCE), against MASLD. Administration of both cyclodipeptides effectively ameliorated metabolic disturbance and hepatic inflammation in high-fat diet-induced MASLD mice, and mitigated lipopolysaccharide-triggered acute inflammation in a complementary in vivo model. Liver transcriptomic analysis revealed that the two cyclodipeptides significantly modulated the hepatic chemokine signaling pathway in MASLD mice. Mechanistically, both cyclodipeptides reduced hepatic CD11b- and F4/80-associated signals and modulated macrophage-associated pro-inflammatory and anti-inflammatory marker expression in vivo and in vitro. Further validation using molecular docking, target inhibitor intervention, drug affinity responsive target stability, cellular thermal shift assay, site-directed mutagenesis, and gene knockout approaches supported that cyclo(Val-Pro) regulated the expression of macrophage C C chemokine receptor type 2 (CCR2), while cyclo(Phe-Phe) modulated adenylyl cyclase 7 (ADCY7), an upstream chemokine signaling regulator, to block downstream inflammatory cascades. Collectively, our findings support further investigation of these two cyclodipeptides and suggest that CCR2- and ADCY7-associated pathways may contribute to their effects in MASLD. Cyclo(Val-Pro) and cyclo(Phe-Phe) ameliorated metabolic dysfunction, hepatic steatosis, and inflammation in HFD-induced MASLD mice, accompanied by attenuation of hepatic macrophage-associated inflammatory signals. These effects may be associated with distinct CCR2- and ADCY7-associated signaling pathways and reduced chemokine-related responses. Download: Download high-res image (145KB) Download: Download full-size image
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Huiru Liu,Songsong Wang,Na Wang,Fang Wang,Jin Ren,Zirong Zhou,Kairui Liu,Xinyan Wang,Yubo Li,Chunsheng Fu,Liwen Han
Ethnopharmacological relevance HeDan Capsules(HD), a traditional Chinese medicinal preparation, possesses the effects of resolving phlegm, reducing turbidity, activating blood circulation, and resolving blood stasis. It is clinically indicated for the treatment of hyperlipidemia and metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanism by which HD ameliorates MASLD remains unclear. Aim of the study This study aims to systematically elucidate the potential mechanisms and key bioactive ingredients underlying the efficacy of HD in ameliorating MASLD. Material and methods Classical rat MASLD model was used to evaluate the therapeutic effects of HD. Non-targeted and targeted quantitative metabolomics approaches were employed to investigate the therapeutic effects of HD from the perspective of bile acid metabolism. Key proteins involved in the bile acid synthesis pathway were identified using RT-qPCR and Western blotting, while differences in gut microbiota composition were analyzed via 16S rDNA sequencing. Network pharmacology combined with Bayesian optimization-based molecular docking was used for screening of active compounds. Molecular dynamics simulations and alanine scanning were subsequently performed to assess binding stability and key residue interactions. Finally, the key active compounds of HD were validated in a zebrafish model, and their mechanism of action was investigated at the cellular level using inhibitors. Results HD improved liver function in the MASLD rat model by enhancing lipid deposition and inflammatory response, and significantly modulated the bile acid metabolic network in rats with MASLD. Subsequent targeted metabolomics analyses further confirmed that HD markedly alter bile acid profiles in rat serum. Results from RT-qPCR and Western blotting suggested that HD might influence the classical bile acid synthesis pathway by acting on the FXR/CYP7A1/CYP8B1 signaling pathway. Sequencing results of 16S rDNA indicated that HD may also influence bile acid metabolism through affecting the stability of the gut microbiota. Ultimately, nuciferine, ursolic acid, cryptotanshinone, quercetin, salvianolic acid A, and methyl tanshinonate were identified as the key active components, and cellular-level experiments further confirmed that the effects of HD could be blocked by an FXR inhibitor. Conclusions HD may effectively reduce hepatic lipid accumulation to ameliorate MASLD. Mechanistically, HD regulates the classical bile acid synthesis pathway through the FXR/CYP7A1/CYP8B1 signaling axis and promotes gut microbiota homeostasis. And this study identified firstly the key bioactive ingredients in HD that underlie its anti-MASLD effect.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
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IF 6.6
Qingyang Li,Wei Zhu,Xiao Han,Peiyu Yang,Changhao Liu,Rubing Zou,Shuying Li,Yihua Liu,Yirong Guo
CPF and TCP showed distinct triglyceride-rich lipidomic profiles. • CPF broadly reprogrammed lipid synthesis and xenobiotic metabolism. • TCP-associated lipid disruption involved mitochondrial energy dysfunction. • Co-exposure increased triglyceride accumulation and expanded gene–lipid networks. Metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasingly linked to environmental chemical exposure, yet the metabolic consequences of pesticide parent–metabolite co-exposure remain poorly understood. HepG2 cells were exposed for 48 h to chlorpyrifos (CPF, 10 mg/L), its major metabolite 3,5,6-trichloro-2-pyridinol (TCP, 1.25 mg/L), or their combination (CTCP). Network toxicology was applied for hypothesis generation, followed by integrated lipidomics and transcriptomics analyses. Under the selected exposure conditions, TCP induced greater lipid-droplet accumulation than CPF despite the lower nominal concentration. Lipidomic profiling revealed that both compounds promoted triglyceride accumulation accompanied by extensive remodeling of cholesterol esters, free fatty acids, phospholipids, and sphingolipids. Transcriptomic analysis indicated that CPF elicited a broader response characterized by CYP-mediated xenobiotic metabolism and lipid-handling pathways, whereas TCP exhibited a more restricted signature associated with energy homeostasis and stress-related pathways. Functional assays further supported these distinct responses, showing that TCP exposure reduced ATP levels and increased reactive oxygen species generation, consistent with disrupted cellular energetic and redox homeostasis, while CPF increased cellular CYP1A2 protein levels. Compared with individual exposures, CTCP was associated with greater lipid accumulation and broader transcriptomic and lipidomic alterations involving membrane remodeling, altered cellular energy homeostasis, and changes in inflammation-associated lipid pathways. CPF and TCP produced distinct but overlapping MASLD-relevant lipid metabolic alterations, and their co-exposure produced greater metabolic alterations than either individual exposure under the tested conditions. These findings highlight the importance of considering pesticide metabolites and parent–metabolite co-exposure in environmental health risk assessment.
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Frontiers in Microbiology
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2026
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IF 5.8
Chengfeng Li,Ying Liu,Sitong Ye,Haihua Zhang,Miao Sun,Yingyan Liao,Yan Lin,Sha Tian,Kun Luo,Zhimin Zhang
BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. The latest research shows that its pathogenesis is closely related to the imbalance of gut microbiota. Prunella vulgaris L. is an edible-medicinal plant containing bioactive compounds such as polyphenols that can lower cholesterol and protect the liver. However, whether it has anti MASLD effects has not been reported. The present study aimed to investigate the effect of Prunella vulgaris polyphenols (PVP) on alleviating MASLD from the perspective of the gut-liver axis.MethodsPVP composition was characterized via UPLC-MS/MS and HPLC. Enzymatic kinetics, fluorescence quenching, and molecular docking were used to study the inhibition of PVP and rosmarinic acid (RA) on cholesterol esterase (CEase). Effects on liver lipid accumulation and intestinal cholesterol transport were assessed using HepG2 and Caco-2 cell models. A MASLD mouse model was evaluated through ELISA, tissue staining, and 16S rRNA sequencing to determine the efficacy and mechanisms.ResultsPVP and RA exhibited anti-competitive inhibition of CEase, with IC50 values of 1.63 ± 0.06 and 0.39 ± 0.17 mg/mL, respectively. RA showed strong binding to CEase. PVP and RA significantly alleviated hepatic lipid accumulation in HepG2 cells, inhibited intestinal cholesterol absorption, and promoted cholesterol efflux in Caco-2 monolayers. In MASLD mice, PVP significantly reduced serum ALT, TBA, and TG, lowered hepatic TC and fecal TBA (P < 0.05), and ameliorated liver pathological damage. In addition, both PVP and RA modified the composition of gut microbiota in the cecum, which characterized by a reduction in bile acid (BA)-related bacteria such as g_UBA7173, g_Bacteroides_H, f_Burkholderiaceae_A, g_Phocaeicola_A, and g_Turicimonas, while increasing f_Lachnospiraceae and f_Oscillospiraceae.ConclusionPVP ameliorates MASLD by inhibiting CEase and intestinal cholesterol absorption, promoting cholesterol efflux, and regulating TBA levels along with intestinal microbiota homeostasis. Our findings suggest that PVP and RA deserve further investigation as potential modulators of cholesterol metabolism in MASLD.
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Food & Function
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2026
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IF 6.3
Ziyuan Zhou,Xiaxia Pan,Jiali Ni,Zhuoqi Lou,Yangfan Shen,Shiman Jiang,Xiangmin Dong,Fengjiao Wang,Yanfei Chen,Lanjuan Li
Existing evidence indicates that pre-existing metabolic dysfunction-associated steatotic liver disease (MASLD) confers susceptibility to acute liver injury (ALI). Nevertheless, the underlying mechanism prompting ALI risk in such condition is not fully uncovered yet. Gut dysbiosis has been well-documented in MASLD patients which prompts us to hypothesize that gut dysbiosis may serve as a contributing factor and regulating target to ALI susceptibility. A case-control study was performed and verified the increased risk of ALI in MASLD patients. Mice pretreated with MASLD mice/patients-derived fecal microbiota transplantation (FMT), demonstrated worsened ALI after D-GalN/LPS injection. We identified significant gut dysbiosis with decreased microbial α-diversity, beneficial genus lactobacillus, increased potential harmful bacteria Campylobacter and helicobacter. Probiotic Akkermansia muciniphila (A. muciniphila) was reported to improve gut dysbiosis. Thus, we tested the effect of A. muciniphila on ALI mice pretreated with MASLD mice-derived FMT. A. muciniphila significantly ameliorated the worsened ALI and improved gut dysbiosis. Transcriptomic analysis reveled that A. muciniphila restored the impaired liver PPAR-α signaling, alleviating the aggravated NF-κB signaling and downstream inflammation response in liver. Specifically, A. muciniphila restored the decreased abundance of PPAR-α agonist daidzein in colon, thereby restoring PPAR-α activation and inhibiting NF-κB signaling in liver. Daidzein is also capable to ameliorate ALI aggravated by MASLD-associated dysbiosis, accompanied by PPAR-α activation and NF-κB inhibition. Our findings revealed that gut dysbiosis in MASLD increased the risk of ALI. A. muciniphila exhibited preventive potential for MASLD patients to reduce ALI risk. Daidzein/PPAR-α/NF-κB signaling is important to maintain host resistance to hepatoxic challenge.
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Food Bioscience
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2025
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IF 5.9
Qile Zhang,Yiu Ming Cheung,Chufeng He,Hoi Wa Yeung,Minghui Li,Xiao Yu Tian,Wing Tak Wong
Metabolic dysfunction-associated steatotic liver disease (MASLD) lacks effective pharmacotherapies. This study evaluated the nutritional interventions of Umbelliferone (UMB), a natural coumarin from fruits, on MASLD using a combination of in vitro colonic fermentation, a high-fat diet (HFD)-induced mouse model, and oleic acid-treated HepG2 cells. Biochemical, histological, and molecular analyses were performed to evaluate metabolic and microbial changes. UMB exhibited prebiotic properties, enhancing microbial diversity and butyrate production. It significantly reduced serum lipids, ALT/AST levels, and hepatic steatosis in HFD-mice. In hepatocytes, UMB activated AMPK signaling, inhibiting lipogenesis and promoting fatty acid oxidation. Furthermore, UMB restored gut microbiota balance and increased short-chain fatty acids. These results indicate that UMB alleviates MASLD by modulating hepatic metabolic function and gut microbiota homeostasis, highlighting its dual therapeutic role targeting the gut–liver axis.
研究领域:
肝病学
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营养生物化学
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微生物组研究
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代谢性疾病
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生药学
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JOURNAL OF NUTRITIONAL BIOCHEMISTRY
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2025
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IF 4.9
Bing Li,Pengjun Zhong,Xueling Zhang,Chengguo Li,Min Luan,Yanlin Chen,Lei Chen,Wu Li,Rihui Wu
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a progressively critical global health concern, with no pharmacological interventions currently approved. Ursodeoxycholic acid (UDCA), an endogenous bile acid utilized in clinical practice, has demonstrated therapeutic potential in treating MASLD. However, the precise mechanisms by which UDCA exerts its hepatoprotective effects in MASLD remain to be fully characterized. We found that UDCA intervention markedly alleviated HFD-induced phenotypes, including hepatic steatosis, inflammation and metabolic disturbances, in high-fat diet (HFD)-fed mice. Mechanistically, UDCA treatment significantly activated hepatic peroxisome proliferator-activated receptor α (PPARα) and Cytochrome P450 family 4 subfamily A member 14 (CYP4A14)-mediated β-fatty acid oxidation. In vitro , treatment with UDCA effectively reduced lipid accumulation and liver enzyme release in AML12 hepatocytes subjected to palmitic acid (PA) and oleic acid (OA) challenge. UDCA administration significantly activated the PPARα-CYP4A14 signaling pathway, however, siRNA-mediated knockdown of these components resulted in a significant reduction of UDCA's protective efficacy in alleviating lipid accumulation in PA/OA-induced cellular models. Additionally, molecular docking and molecular dynamics simulations demonstrated stable interactions between UDCA and CYP4A14, indicating that UDCA may directly regulate CYP4A14 signaling. In conclusion, this study elucidates the CYP4A14-involved PPARα signaling as a novel mechanism by which UDCA exerts its anti-MASLD effects, thereby providing a theoretical foundation for considering UDCA as a potential therapeutic agent for MASLD.
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Nature Communications
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2026
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IF 18.1
Wen Xiao,Wu Keyan,Wang Mengyao,Ma Zihan,Wang Tao,Zhang Jing,Wang Bei,Chen Siyuan,Wang Jingyi,Chen Siyue,Yang Fan,Liu Chuwei,Chen Xianyang,Deng Lu,Cheng Yafan,Miao Qing Robert,Sun Baofa,Ruan Xiongzhong,Li Kai,Duan Yajun,Hu Wenquan
Inflammation is a pivotal driver of the progression from metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), an aggressive form associated with substantial liver-related mortality. However, the molecular mechanisms underlying the initiation and persistence of liver inflammation remain poorly defined. Here, we demonstrated a previously unrecognized role for hepatic acetyl-CoA synthetase short-chain family member 2 (ACSS2) in MASH, showing that ACSS2 upregulation in patients exacerbates MASH progression by functioning as an epigenetic regulator, independent of its canonical lipogenic role. Mechanistically, ACSS2, in complex with lysine acetyltransferase 5 (KAT5), upregulates allograft inflammatory factor-1 ( AIF1 ) transcription via histone crotonylation, thereby inducing liver inflammation and subsequently resulting in the aberrant accumulation of senescent hepatocytes, which further enhances proinflammatory cytokine production. This ultimately initiates a vicious cycle of chronic inflammation, which directly promotes the progression from simple steatosis to MASH. Thus, our work reveals a mechanistically defined and pivotal role for ACSS2 in promoting the MASLD-to-MASH transition, highlighting its potential as a compelling therapeutic target.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Gang Wei,Kai Zhang,Feng-Jie Shen,Rong-Rong Xie,Feng-Wei Wang,Hua-Qi Guo,Lin Liu
The global incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has surged in recent years, potentially impacted by both high-energy food intake (e.g., high-fat diet, HFD) and environmental pollutants like microplastics (MPs). However, the combined impacts of MPs exposure and HFD feeding, particularly under long-time exposure, low concentrations MPs conditions, on the MASLD progression remain to be fully elucidated. In this study, C57BL/6 J male mice were fed either a normal chow diet or HFD with or without low-dose MPs (polystyrene) exposure (25–30 μg/kg body weight /day) for 14 weeks. The adverse health effects associated with MASLD development were evaluated, including intestinal permeability, gut microbiota composition, hepatic lipid metabolism, and the mediating role of the gut-liver axis. Additionally, HFD with or without low-dose MPs exposure was withdrawn to further verify this process. Our data demonstrated that low-dose MPs exposure or HFD feeding significantly increased the gut permeability, oxidative stress, pro-inflammatory response and apoptosis, while concurrently contributing to gut dysbiosis (e.g., reduced levels of Akkermansia ) and MASLD development. Furthermore, low-dose MPs exposure exacerbated these effects in combination with HFD feeding, exhibiting a ‘double hit’ effect. Notably, the impacts of low-dose MPs exposure combined with HFD feeding on MASLD were difficult to reverse after two weeks withdrawing, likely due to the limited recovery potential of intestinal barrier integrity and gut microbiota homeostasis. These finding underscore the importance of avoiding MPs exposure in the pathogenesis of MASLD, particularly under a metabolic disorder conditions, and provide valuable insights for the developing therapeutic strategies to combat MASLD caused by MPs exposure.
研究领域:
医学
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生物学
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环境科学
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