Kunzao Tiaozhi capsule ameliorates MASLD
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Yiyuan Zheng
PROVIDER: PXD077683 | iProX | Mon Apr 27 00:00:00 BST 2026
REPOSITORIES: iProX
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Project description:To investigate the mechanism by which ONX‑0914 ameliorates MASLD, HFD‑fed mice were randomized to receive the selective PSMB8 inhibitor ONX‑0914 (10 mg/kg in 10% captisol, s.c., every other day) or vehicle control for an additional 6 weeks while remaining on the HFD. At the experimental endpoint, liver tissues were collected for RNA sequencing.
2026-04-02 | GSE326369 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a clinicopathological syndrome characterized by abnormal accumulation of fat within hepatocytes, and there is currently no standardized clinical treatment available. Consequently, there is an urgent need to discover new pharmacological interventions and to investigate novel therapeutic targets for MASLD. Melatonin, known for its multifaceted biological functions, has shown therapeutic potential for the treatment of MASLD. However, the underlying mechanisms remain unclear, particularly since the direct targets of melatonin have not yet been discovered. In our study, we found that melatonin significantly improved various indicators in a mouse MASLD model and protected palmitic acid induced mouse hepatocytes from lipid accumulation. We successfully identified and validated the mitochondrial trifunctional enzyme α-subunit HADHA as a binding target for melatonin using the cellular thermal shift assay (CETSA). This interaction enhances the expression of PGC-1α, which subsequently promotes mitochondrial biogenesis and accelerates lipid metabolism. In addition, melatonin reduces lipid accumulation and ameliorates MASLD through its regulatory effect on key proteins involved in fatty acid metabolism, including Acyl coenzyme A oxidase 1, CD36, and Fatty acid synthase. Importantly, these beneficial effects are diminished when HADHA is knocked down. In conclusion, our study suggests that melatonin ameliorates MASLD through HADHA-mediated regulation of mitochondrial biogenesis and lipid oxidation, highlighting its potential as a promising therapeutic agent for MASLD. These results lay a theoretical foundation and offer novel insights and strategies into the role of melatonin in the treatment of MASLD.
2026-06-08 | PXD071550 | Pride
Project description:Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread and severe hepatic disease, affecting approximately 30% of the global population. Despite its prevalence, the precise pathophysiological mechanisms underlying the development of MASLD remain incompletely elucidated. Previous investigations have revealed that A1M exerts regulatory effects on endoplasmic reticulum stress and oxidative reactions within hepatocytes, thereby affecting liver homeostasis. However, the roles of AMBP, the precursor of A1M and Bikunin, in the pathogenesis and progression of MASLD remain inadequately characterized. Methods: In this study, we analyzed the AMBP expression across multiple MASLD related Gene Expression Omnibus (GEO) datasets. Utilizing zebrafish ambp-/- and mouse Ambp-/- mutants subjected to high-fat diet (HFD) feeding, we assessed hepatic lipid accumulation. Additionally, we measured reactive oxygen species (ROS) levels, glutathione peroxidase 4 (Gpx4), and malondialdehyde (MDA) expression, and performed RNA sequencing in HFD-fed ambp-/- zebrafish. The roles of ROS were further investigated using the ROS inhibitor N-acetylcysteine (NAC) and the PPARα-specific inhibitor GW6471. Results: Our finding revealed that ambp deficiency mitigated the occurrence of MASLD under HFD conditions. Mechanistically, ambp deficiency induced the production of cytoprotective ROS, which subsequently activated the PPAR signaling pathway, thereby inhibiting oxidative stress and enhancing the mitochondrial fatty acid β-oxidation. Conclusions: Collectively, our results demonstrate that AMBP serves as a critical regulator of MASLD pathogenesis. Inhibition of AMBP might be a promising therapeutic approach for the treatment of MASLD.
2026-06-10 | GSE292291 | GEO
Project description:Animal models are essential to understand the mechanisms underlying the onset and progression of metabolic associated steatotic liver disease (MASLD), a rapidly growing form of chronic liver disease driven largely by the global rise in metabolic syndrome. However, existing animal models for MASLD often fail to accurately reproduce advanced human liver disease, and have varying degrees of clinical relevance. To address this, we have undertaken efforts to create a dietary translational model of MASLD in rats that closely replicates the full MASLD phenotype observed in humans, including advanced fibrosis, portal hypertension, and metabolic syndrome. Three MASLD rat models were developed by sequentially combining a high-fat glucose-fructose diet (HFGFD) with additional factors: lipopolysaccharide, increased cholesterol (Chol), and cholic acid (CA) at different concentrations. Of these, two diets—D4-MASLD (HFGFD + 2% Chol) and D5-MASLD (HFGFD + 2% Chol + 0.1% CA)—effectively replicated MASLD characteristics. Transcriptomic analysis revealed that while both diets significantly altered gene expression compared to controls, D5-MASLD had a greater impact on the activation of inflammation and immune response pathways. The inclusion of CA in D5-MASLD exacerbated pathways related to microbiota changes, intestinal barrier dysfunction, and bacterial translocation. Additionally, comparison of the transcriptomic profiles of these diet-induced rat models with data from MASLD/MASH patients further validated the relevance of these models, establishing a robust platform for studying MASLD pathogenesis and evaluating potential therapeutic interventions.
2026-04-20 | GSE282001 | GEO
Project description:Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a growing global health concern. Increased de novo lipogenesis (DNL), largely mediated by Sterol Regulatory Element-Binding Protein 1 (SREBP1), is a hallmark of MASLD. However, the post-translational mechanisms regulating SREBP1 turnover remain poorly understood. The endoplasmic reticulum-associated degradation (ERAD) pathway ensures protein quality and quantity control, yet its role in hepatic lipid metabolism remains elusive. Here, we investigate the function of the ERAD-specific E3 ubiquitin ligase MARCHF6 in hepatic lipid homeostasis and MASLD pathogenesis.We found hepatic MARCHF6 expression was significantly reduced in both MASLD mouse models and human patients. Liver-specific Marchf6 deletion aggravated hepatic lipid accumulation, fibrosis, and inflammation. Transcriptomic and proteomic analyses revealed upregulation of lipogenic genes in Marchf6Alb livers, with a marked increase in SREBP1 protein levels. Mechanistically, MARCHF6 directly interacted with and ubiquitinated SREBP1, targeting it for proteasomal degradation. Loss of MARCHF6 prolonged SREBP1 half-life, driving excessive DNL.
2026-05-28 | GSE319144 | GEO
Project description:Background: N6-methyladenosine (m6A) RNA modification plays a crucial role in various biological events and is implicated in various metabolic-related diseases. However, its role in MASLD remains unclear. This study aims to investigate the impact of Mettl3 on MASLD through multi-omics analysis, with a focus on exploring its potential mechanisms of action. Methods: MASLD mouse models were established by feeding a high-fat diet for 12 weeks, and Mettl3 stable overexpression AML12 cell models were constructed via lentiviral transfection. Subsequent transcriptomic and proteomic analyses, as well as integrated analysis between different omics datasets, were conducted. Results: Mettl3 expression significantly increased in MASLD mouse models. In the transcriptomic and proteomic analyses, we identified 848 genes with significant inconsistencies between transcriptomic and proteomic datasets. GO/KEGG enrichment terms may involve post-transcriptional modifications, particularly Mettl3-mediated m6A modification. Subsequently, through integrated proteomic analysis of Mettl3-overexpressed AML12 cell models and MASLD mouse models, we selected the top 20 co-upregulated and co-downregulated GO/KEGG terms as the main biological processes influenced by Mettl3 in MASLD. By intersecting with pathways obtained from previous integrated analyses, we identified GO/KEGG terms affected by Mettl3-induced m6A modification. Protein-protein interaction analysis of proteins involved in these pathways highlighted GAPDH, ENO1, and TPI1 as three key hub genes. Conclusion: In MASLD, Mettl3 regulates the glycolytic pathway through m6A modification, influencing the occurrence and development of the disease via the key hub genes GAPDH, ENO1, and TPI1. These findings expand our understanding of MASLD and provide strong evidence for potential therapeutic targets and drug development.
2024-09-20 | PXD050565 | Pride
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by imbalance of lipid metabolism and autoimmune inflammation. The relationship between Hypoxia-inducible Factor 2α (HIF-2α) and the progression of MASLD has been well-documented. However, the mechanistic linkage between HIF-2α and steatohepatitis progression remains largely elusive. Here, hepatocyte-specific HIF-2α knockout mice were used to identify underlying pathophysiological relevance in MASLD. Through multiple gain- and loss-of-function experiments in primary hepatocytes and established human hepatocyte cell lines to investigate the molecular mechanism of HIF-2α in MASLD progression. Compared to their wild-type littermates, hepatocyte-specific HIF-2α knockout mice exhibited a substantial reduction in hepatic steatosis and inflammatory pathway induced by high fat diet (HFD). Furthermore, the HIF-2ɑ deficiency in primary hepatocytes and both L02 and MIHA cell lines markedly inhibited the lipid accumulation, inflammation and endoplasmic reticulum stress in vitro under FFAs challenge. Mechanistically, HIF-2 directly bound to the promoter region of protein kinase RNA-like ER kinase (PERK), leading to the activation of the activating transcription Factor 4 (ATF4) signaling under metabolic stress, thereby aggravating lipogenesis while inhibiting lipid oxidation in hepatocytes.These data indicate that HIF-2α acts as a contributing factor to MASLD progression via ATF4 signaling.
2025-12-10 | GSE267155 | GEO
Project description:This study aimed to establish and characterize an in vitro model of human intestinal organoids isolated from duodenal samples of patients with non-fibrotic MASLD and those with MASLD-cirrhosis. Whole transcriptome analysis and the energetic and redox status of the organoids were assessed to characterize intestinal functional impairment in the context of MASLD. We used microarrays to detail the whole transcriptome dysregulation underlying intestinal dysfunction in organoids isolated from chirrotic versus non-fibrotic MASLD patients.
2025-09-04 | GSE299719 | GEO
Project description:Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a leading cause of hepatocellular carcinoma and liver transplantation worldwide, making identification of intervention strategies and therapeutic treatments essential to reducing morbidity and mortality associated with this disease. RNA binding proteins, like human antigen R (HuR), are ubiquitous and multi-faceted cell-stress regulators. HuR’s role in MASLD development is incompletely understood. This study aims to determine how hepatocyte HuR deficiency drives MASLD progression to Metabolic dysfunction-associated steatohepatitis (MASH). To model MASLD, we fed male hepatocyte-specific HuR knockout mice (HuRHep-/-) and WT control mice with the normal chow diet or the MASLD-inducing high fat, cholesterol, and fructose (HFCF) diet for 16 weeks. The liver transcriptomic profile was mapped using bulk RNA sequencing (RNA seq). After MASLD-inducing diet feeding, bile acid metabolism was modulated, while liver injury and fibrosis markers were increased in male HuRHep-/- mice, relative to WT. Our data suggests that hepatocyte HuR deficiency dysregulates bile acid metabolism and exacerbates MASLD progression.
2026-06-03 | GSE287727 | GEO
Project description:Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver-related morbidity and mortality. Premenopausal women have a lower MASLD risk than postmenopausal women. G protein-coupled estrogen receptor 1 (GPER1) exerts hepatic protective effects, and GPER1 specific agonist (G1) has shown preclinical potential in improving metabolic disorders. However, clinical studies on G1’s metabolic benefits and GPER1’s clinical relevance in human liver tissue remain unclear. This study aims to bridge basic and clinical research by validating G1’s efficacy in ameliorating MASLD-related hepatic steatosis, exploring its molecular mechanisms, and clarifying GPER1’s association with human MASLD. Methods We investigated the expression of GPER1 in human liver tissue and its correlation with the severity of steatosis. The function of GPER1 was validated both in vitro (using a free fatty acid-induced hepatocyte steatosis model treated with the GPER1 agonist G1 or antagonist G15) and in vivo, with assessments of lipid metabolism-related genes, reactive oxygen species, and apoptosis. GPER1-associated proteins were identified through proteomic sequencing and co-immunoprecipitation. Results GPER1 is lowly expressed in MASLD patients, negatively correlating with steatosis severity. G1 upregulates GPER1, alleviates hepatocyte steatosis and lipid deposition, modulates lipid metabolism-related proteins, ameliorates hepatic steatosis, and interacts with GAIP-interacting protein C-terminal 1 (GIPC1). G15 antagonizes these beneficial effects. Conclusions Based on clinical data, this study shows that low GPER1 expression correlates closely with hepatic steatosis in MASLD. The GPER1 agonist G1 ameliorates hepatic steatosis via multiple GPER1-dependent mechanisms, including regulating lipid metabolism, suppressing oxidative stress, and reducing apoptosis. Notably, GIPC1 may be involved in the GPER1-mediated regulatory pathway, and its role in this context merits further investigation.
2026-03-09 | PXD075389 |