BackgroundHypericum perforatum L. (Guan Ye Jin Si Tao, GYJST), commonly known as St. John’s wort, is a widely distributed medicinal plant across Europe and Asia. Preclinical studies have identified its therapeutic potential in both neurological and metabolic disorders. However, its impact on metabolic-associated fatty liver disease (MAFLD) remains unclear. This study comprehensively investigated the therapeutic effects of GYJST on MAFLD through both invivo and in vitro experiments. Utilizing a multi-omics approach, the research elucidated the regulatory mechanisms of GYJST on ferroptosis, focusing on oxidative stress, lipid metabolism, and inflammatory response modulation. The findings provide valuable insights into the potential therapeutic applications of GYJST in managing MAFLD.Materials and methodsLiver assessments were systematically conducted to evaluate the therapeutic effects of GYJST on HFD-induced mice and PA-induced AML12 cells. Comprehensive histological analyses, including H&E, Masson, Sirius Red, Oil Red O, and F4/80 staining, were performed to assess the impact of GYJST on liver pathology. To elucidate the underlying mechanisms of GYJST, a multi-omics approach was employed, integrating network pharmacology, transcriptomics, proteomics, and metabolomics. Additionally, RT-qPCR, western blotting, and immunofluorescence techniques were utilized to validate the effects of GYJST.ResultsGYJST effectively protects against liver injury by mitigating inflammation, oxidative stress, and lipid metabolism dysregulation. A total of 90 major compounds in GYJST were tentatively identified. Network pharmacology analysis revealed its multi-target, multi-pathway mechanisms of action. Integrative transcriptomic, metabolomic, and proteomic analyses consistently highlighted pathways associated with inflammatory responses, oxidative stress, and lipid metabolism. Mechanistically, GYJST suppresses systemic inflammation via the NF-κB/COX-2 signaling axis and alleviates oxidative stress and lipid accumulation through the Nrf2/PPARα/g pathway. Additionally, GYJST plays a crucial role in inhibiting ferroptosis, partly through Nrf2-mediated mechanisms.ConclusionGYJST exerts multi-target therapeutic effects against MAFLD by concurrently regulating ferroptosis, oxidative stress, lipid metabolism, and inflammation through interconnected mechanisms. These findings establish GYJST as a promising multi-target therapeutic candidate for MAFLD treatment.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s13020-025-01248-1.

Metabolic-associated fatty liver disease (MAFLD) is a progressive metabolic disorder characterized by hepatic steatosis, inflammation, and fibrosis. Emerging evidence suggests that lactate-driven histone lactylation may contribute to its pathogenesis, but mechanisms remain unclear. C57BL/6 mice were fed HFD or CDHFD, and hepatocytes were treated with OAPA. Histone lactylation was assessed by IF and WB. CUT&Tag and RNA-seq identified downstream targets, while H4K16R mutation, PDK4 knockdown, and dichloroacetic acid (DCA) inhibition were applied in vitro and in vivo. Histone lactylation, especially H4K16la, was elevated in murine and human MASH and correlated with steatosis, inflammation, and fibrosis. H4K16la directly activated PDK4 transcription, forming a lactate-H4K16la-PDK4 feedback loop that exacerbated MAFLD. Genetic or pharmacologic inhibition reduced lactate, lipid accumulation, and liver injury. We identify a lactate-H4K16la-PDK4 axis that drives metabolic reprogramming and MAFLD progression. Targeting PDK4 may represent a therapeutic strategy for MAFLD/MASH.

Hepatocellular carcinoma (HCC) is the primary liver tumor that arises from various risk factors, including hepatitis, excessive alcohol consumption, and obesity. These risk factors induce pathophysiological alterations in the liver, such as inflammation, fibrosis, cirrhosis, fatty liver, abnormal regeneration, and angiogenesis. Although procedures like ablation and transplantation hold promise for addressing this malignancy, the recurrence and metastasis rates limit the long-term efficacy of these surgical interventions. Thus, natural compounds exhibit great potential in enhancing clinical interventions, managing the disease effectively, and improving survival rates in HCC. Compounds such as silymarin, silibinin, resveratrol, curcumin, quercetin, genistein, naringenin, cucurbitacin, lycopene, crocin, aronia, Nigella sativa, epigallocatechin-3-gallate, and ginger (Zingiber officinale) demonstrate promise in HCC treatment, primarily through mechanisms involving the suppression of inflammation, regulation of oxidative stress, and promotion of apoptosis. This study searched PubMed, Scopus, Web of Science, Google Scholar, and ClinicalTrials.gov databases to evaluate the molecular mechanisms by which natural compounds are associated with HCC. The literature search was performed using the keywords "hepatocellular carcinoma," "angiogenesis," "inflammation," "oxidative stress," "natural products," and "apoptosis." By evaluating the findings cumulatively, the aim was to reveal the up-to-date scientific evidence for using natural compounds as potential therapeutic agents in treating HCC.

Abstract Background Obesity and metabolic syndrome are major health issues nowadays. These problems are linked to visceral adipose tissue (VAT) and sarcopenia (muscle loss). Investigating the connection between VAT and sarcopenia in women with prediabetes and recently diagnosed type 2 DM (T2D) was the aim of this study. Methods The study included 44 women aged 40–60 who were either prediabetic or had just been diagnosed with T2D and had not started treatment yet. Researchers used CT scans to quantify VAT and muscle mass, conducted medical tests, and looked at other metabolic risk factors. Results The study included 44 women with a mean age of 45.5 years: 34% had T2D and 66% were prediabetic. Hypertension was present in 38.6% of patients, and 65.9% met the criteria for metabolic syndrome. VAT volume was positively correlated with indicators of fatty liver, insulin resistance, and triglyceride levels. However, VAT volume did not significantly differ between participants with and without metabolic syndrome. Notably, muscle strength was lower among those with metabolic syndrome, although muscle mass did not differ substantially. Conclusion Cardiometabolic risk factors, including obesity, insulin resistance, and elevated triglycerides, are associated with increased visceral adiposity and reduced muscle strength, but not reduced muscle mass. These findings support the clinical utility of CT-derived visceral fat assessment and highlight the importance of evaluating muscle function rather than relying solely on BMI when assessing metabolic health and sarcopenia risk in prediabetic and diabetic patients.

Isoliquiritigenin inhibits the activation of the ANXA2/STAT3 pathway by down-regulating TAGLN2, thereby alleviating alcoholic fatty liver.

Metabolic dysfunction-associated steatotic liver disease, cardiometabolic risk factors, and cardiovascular disease.

How to define low muscle mass: A critical exploration of current definitions supports a reference equation-based approach.

Fibroblast growth factor receptor inhibitors ameliorate metabolic dysfunction-associated steatohepatitis by modulating the glycine-glutathione-gut microbiota axis.

Background:Metabolic dysfunction–associated steatotic liver disease (MASLD) affects ~30% of the US adult population, and its prevalence is increasing. Early-stage disease is often missed by clinicians as it is largely asymptomatic until cirrhosis develops. Recent advances in artificial intelligence (AI) have allowed for expanded electronic health record (EHR) identification of several diseases. We aimed to develop an algorithm that utilizes AI to identify patients with MASLD via a large-scale review within the EHR.Methods:We created a natural language processing (NLP) algorithm that identifies patients with hepatic steatosis on abdominal imaging and selects for patients meeting MASLD criteria. Validation was carried out via manual review of monthly generated cohorts. The algorithm was then utilized to retrieve a MASLD cohort for initial analysis. Demographics were summarized, and additional variables pertaining to early MASLD management were analyzed.Results:Our algorithm identified patients with MASLD with a positive predictive value (PPV) of over 93%. The NLP component of the algorithm identified hepatic steatosis in imaging reports with a PPV of up to 99.4% and excluded patients with alcohol use with a negative predictive value of ~95%. From a cohort spanning 6 months, 957 individuals with MASLD were identified by the algorithm, of which 14.6% (n=140) had a MASLD-related diagnosis code.Conclusions:We developed an AI algorithm that can perform a large-scale review of electronic health records to identify patients with MASLD with >93% accuracy. Our initial analysis suggests that a substantial proportion of individuals meeting MASLD criteria do not yet carry a MASLD-related diagnosis. Our work can be adapted by other institutions to enhance the detection of MASLD and alcohol use patterns, allowing for targeted interventions to prevent disease progression and improve outcomes.

Daidzein-betaine cocrystal alleviates high-energy and low-protein diet induced fatty liver hemorrhagic syndrome in laying hens through gut-liver axis.

Italian SIGENP (Italian Society of gastroenterology, hepatology and pediatric nutrition) registry of pediatric home artificial nutrition: First report.

CIDEB (cell death-inducing DFF45-like effector B) deficiency is associated with a reduced incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) in humans; however, the underlying mechanism responsible for this protective effect remains unclear. C57BL/6J male mice were fed a high-fat diet (HFD) to recapitulate key aspects of MASLD and hepatic insulin resistance. Cideb knockdown (KD) was achieved using a 2'-O-methoxyethyl (MOE) antisense oligonucleotide (ASO). In vivo rates of hepatic mitochondrial gluconeogenesis and tricarboxylic acid (TCA) cycle flux were assessed by Q-Flux. The Comprehensive Lab Animal Monitoring System (CLAMS) was used to evaluate rates of whole-body energy expenditure. Hepatic and peripheric insulin sensitivity were evaluated using hyperinsulinaemic-euglycaemic clamp studies combined with radio-labelled isotopes. We showed that Cideb ASO treatment increased rates of whole-body energy expenditure by ~25% and decreased hepatic triacylglycerol by ~65% in a HFD mouse model of MASLD compared with the wild-type mice. Cideb KD reduced hepatic fat content, which could mostly be attributed to increased rates of hepatic mitochondrial oxidation, in combination with reduced hepatic lipogenesis. Additionally, Cideb KD ameliorated HFD-induced insulin resistance, which could be attributed to decreased plasma membrane sn-1,2-diacylglycerols (DAGs)-protein kinase C (PKC)ε-insulin receptor kinase (IRK)T1150 phosphorylation in liver and skeletal muscle. These findings demonstrate that Cideb KD enhances mitochondrial fat oxidation and reduces hepatic lipogenesis, which in turn mitigates HFD-induced hepatic steatosis and insulin resistance via the plasma membrane sn-1,2-DAGs-PKCε-IRKT1150 pathway, highlighting its potential as a novel therapeutic approach for MASLD and type 2 diabetes.

The MLL4: Roles in cell differentiation, adipogenesis and cancer.

There is no safe level of exposure to air pollution, including particulate matter smaller than 2.5 µm (PM2.5), to human health. Whilst it is well known that exposure to heavily polluted air is associated with several liver disorders, it is unclear how long-term exposure to low-level traffic-derived PM2.5 affects liver health. BALB/c mice (5 weeks, male) were exposed to traffic-derived PM2.5 (10 µg/mouse/day, intranasally) daily for 4, 8 and 12 weeks. Markers of inflammation and fibrosis were measured at each time point. Changes in liver proteome and lipid profiles were measured using proteomics and lipidomics at 12 weeks. Low-dose PM2.5 exposure increased macrophage infiltration, pro-inflammatory cytokine production, and increased collagen deposition at 12 weeks. Despite liver lipid metabolism being increased, the abundance of triglycerides, precursor diacylglycerols, and ceramide was also significantly increased by PM2.5 exposure, whereas glycogen content was reduced. Proteomics analysis revealed 64 proteins to be significantly changed in PM2.5-exposed mice, and KEGG pathway enrichment analysis indicated their involvement in lipid metabolism, alcohol-related liver disease, neutrophil extracellular trap formation, and transcriptional dysregulation related to cancer. In conclusion, prolonged exposure to low-dose traffic-derived PM2.5 promotes pathological changes in the liver, suggestive of an increased risk of metabolic dysfunction-associated fatty liver disease. Future studies can enable the identification of the signalling pathways underlying low-dose PM2.5-induced lipid accumulation in the liver.

High-throughput screening reveals paeoniflorin's efficacy against Apoc2-deficient hypertriglyceridemia via HNF4A/PPARA/LDLR.

Consumption of Brazilian palm fruit (Acrocomia intumescens drude) improves biochemical and gut microbiome parameters, reducing cardiovascular risk in exercised rats.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the new name for nonalcoholic fatty liver disease (NAFLD). MASLD continues to be a significant global health care problem, commensurate with the increased prevalence of obesity and metabolic syndrome. The study of MASLD has intensified over the past 5 years, with major breakthroughs in understanding the pathogenesis and natural history. The American Association for the Study of Liver Diseases (AASLD) published practice guidance in 2023 to incorporate changes in diagnosis and management. A new nomenclature for MASLD, with updated definitions, has been approved through a global multisociety-led Delphi consensus to replace NAFLD with MASLD and nonalcoholic steatohepatitis (NASH) with metabolic dysfunction-associated steatohepatitis (MASH). AASLD practice guidelines on blood-based and imaging-based noninvasive liver disease assessments of hepatic fibrosis and steatosis have also been recently published. The latest advances in US and MRI techniques have allowed radiologists to play a pivotal role in early detection, accurate assessment, and monitoring of diseases, thus enabling timely intervention and lifestyle changes. Resmetirom has recently been approved for treating noncirrhotic adult patients with MASLD and moderate to severe hepatic fibrosis, along with diet and exercise. The authors review the role of imaging in the new guidelines as the current evaluation of MASLD transitions from invasive tests to advanced imaging-based diagnostics. The article will serve as a reference for radiologists, who play a critical role in managing and prognosticating MASLD. ©RSNA, 2025 Supplemental material is available for this article.

Neonatal liver-derived FTH1-enriched extracellular vesicles attenuate ferroptosis and ameliorate MASLD pathogenesis.

Semaglutide, a GLP-1 receptor agonist, is FDA-approved for managing type 2 diabetes (T2D) and reducing cardiovascular risk. Its off-label use in weight management and other conditions has grown, prompting a review of its benefits and risks. This review evaluates evidence on semaglutide's effects, highlighting its therapeutic potential beyond approved indications. Studies from 2021-2024 were reviewed via PubMed, ScienceDirect, and Google Scholar. Semaglutide showed promise in managing PCOS-related obesity, insulin resistance, and demonstrated renoprotective effects in diabetics and chronic kidney disease (CKD). Additionally, it improves liver enzyme levels, steatosis, and stiffness, aiding in managing Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in non-fibrotic patients. The FDA has approved it for reducing major adverse cardiovascular events, heart failure symptoms, and physical limitations in diabetic and non-diabetics. Preclinical studies suggest benefits in cognitive disorders associated with insulin resistance, including Alzheimer's disease, Parkinson's disease, and vascular dementia in animals. Although rare cases of thyroid cancer have been reported, no causal relationship has been established, emphasizing the need of caution in high-risk populations. GLP-1 therapy has also exerted protective effects against the risk of various types of cancer. However, ongoing human studies are essential to validate these findings and clarify semaglutide's association with cancer.

Effect of radiation dose on quantification of the liver iron and fat fractions using dual-energy computed tomography and material decomposition