Search Results (1,070)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease, and its progressive inflammatory phenotype, metabolic dysfunction-associated steatohepatitis (MASH), is characterized by hepatocellular injury, inflammation, and fibrosis. These processes are closely linked to altered metabolite networks, including lipotoxic lipids, oxidized lipid mediators, bile acids, amino acids, acylcarnitines, redox-related metabolites, gut-derived metabolites, and extracellular matrix remodeling products. The recent introduction of resmetirom and semaglutide for MASH with moderate-to-advanced fibrosis provides two complementary models for interpreting these networks. Resmetirom, a liver-directed thyroid hormone receptor-β agonist, primarily enhances intrahepatic lipid handling, mitochondrial fatty acid metabolism, cholesterol turnover, and lipoprotein remodeling. Through this “inside-out” mechanism, resmetirom may reduce hepatocyte lipotoxic stress and secondarily attenuate inflammatory and fibrogenic signaling. Semaglutide, a glucagon-like peptide-1 receptor agonist, mainly acts through systemic metabolic unloading by reducing energy intake, body weight, insulin resistance, and adipose–liver substrate flux. Through this “outside-in” mechanism, semaglutide may improve the hepatic metabolite environment indirectly. However, histological improvement does not by itself establish causal metabolite mediators, and many specific metabolite-level mechanisms remain incompletely defined in human MASH. This review summarizes metabolite networks linked to inflammation and fibrosis in MASLD/MASH, compares the metabolic implications of resmetirom and semaglutide, and discusses how therapeutic metabolomics may support biomarker discovery, patient stratification, and precision pharmacotherapy. Full article

Despite the traditional application of Sophora moorcroftiana (Benth.) Baker seeds for liver disorders, the capacity of its 70% ethanol extract (SMS) to alleviate metabolic dysfunction-associated steatotic liver disease (MASLD) and the underlying gut–liver axis mechanisms remain unclear. In this study, a high-fat diet (HFD)-induced MASLD mouse model was established to investigate the protective effects of SMS and its regulatory role in the interplay among gut microbiota, short-chain fatty acids (SCFAs), and inflammation. Serum, intestinal, and hepatic samples were collected to evaluate inflammatory responses, intestinal barrier integrity, and hepatic lipid metabolism. Gut microbiota composition and SCFA profiles were analyzed using 16S rRNA sequencing and metabolomics. In LPS-stimulated Caco-2 cells, SMS reduced inflammatory cytokines and TLR4/MyD88/NF-κB-associated signaling. The results demonstrated that SMS markedly alleviated hepatic steatosis by reducing triglyceride synthesis and hepatocellular lipid accumulation. In addition, SMS promoted the proliferation of beneficial bacteria, including Bifidobacterium and Akkermansia, and increased the production of SCFAs, particularly butyrate. SMS also restored intestinal barrier integrity through upregulation of Occludin and Claudin-1, thereby reducing circulating lipopolysaccharide (LPS) levels. Furthermore, SMS attenuated inflammation by inhibiting activation of the TLR4/NF-κB signaling pathway. Collectively, these findings demonstrate that SMS alleviates MASLD through coordinated modulation of gut microbiota composition, SCFA metabolism, intestinal barrier function, and inflammatory responses, highlighting its potential as a therapeutic strategy targeting the gut–liver axis. Full article

Background/Objectives: Magnesium (Mg) deficiency has been linked to various adverse health outcomes; however, its association with metabolic dysfunction-associated steatotic liver disease (MASLD) has not been fully elucidated. This study examined the association of serum Mg levels with MASLD in Korean adults. Methods: We analyzed a nationwide sample of 4952 adults in South Korea. Serum Mg levels (mg/dL) were measured. MASLD was defined as a hepatic steatosis index score of ≥36 together with the presence of cardiometabolic risk factor, including overweight/obesity, high fasting glucose, high blood pressure, high plasma triglycerides, or low plasma HDL cholesterol. The association between serum Mg levels and MASLD was examined using logistic regressions. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined. Results: The mean (standard deviation [SD]) serum Mg level was 2.13 (0.15) mg/dL. The prevalence of MASLD was 25.7%. After adjusting for the sociodemographic variables, the OR (95% CI) for the association between a 1–SD increment in serum Mg levels and MASLD was 0.90 (0.84–0.96, p = 0.004). Conclusions: This nationally representative cross-sectional study found that serum Mg levels were inversely associated with the likelihood of MASLD among adults in South Korea. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by excessive fat accumulation in the liver (steatosis) and affects approximately 38% of adults globally. MASLD may progress from simple steatosis to fibrosis and cirrhosis and is closely related to other cardio-metabolic conditions (e.g., obesity and type 2 diabetes), posing a risk factor for cardiovascular disease. Currently, lifestyle modification and weight reduction remain the main initial treatment options. Existing data suggest that there is low awareness among patients regarding MASLD diagnosis and its subsequent management. Therefore, this study aimed to develop a rich understanding of the lived experiences, concerns, and support needs of adults with MASLD. Methods: A qualitative design was applied, utilizing semi-structured interviews. Adults living with MASLD were invited to talk about their diagnosis and discuss their lived experiences. Participants were interviewed by telephone or video call, and each interview was transcribed and analyzed with a reflexive thematic analysis approach. Results: Twenty-five adults with MASLD (age range: 24–79 years; 40% men) were interviewed. The emergent key themes related to communication and emotions at diagnosis; independently seeking further information; lived experiences post-diagnosis; support needs; and future concerns. Many participants reported receiving the diagnosis incidentally, and a number of issues were raised regarding lack of clarity at the point of diagnosis. Additional concerns included information obtainable via the internet, symptoms, social relationships, stigma, and lifestyle modification. Future anxieties related mainly to fears of disease progression, while support needs were predominantly focused on information and follow-up. Conclusions: The concerns and support needs identified by this study highlight key issues/themes that should inform education and support initiatives by relevant healthcare services aiming to improve the lived experiences and holistic management of adults with MASLD. Full article

Type 2 diabetes mellitus (T2DM) is often linked to metabolic dysfunction-associated steatotic liver disease (MASLD), a metabolic liver condition defined by excessive lipid deposition within hepatocytes and is frequently accompanied by increased circulating liver enzyme levels. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as linagliptin, may exert pleiotropic effects on hepatic metabolism; however, their effects on liver enzyme profiles remain uncertain. This systematic review and meta-analysis aimed to evaluate the impact of linagliptin on liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT), in patients with T2DM. A systematic literature search was performed across five electronic databases up to 11 May 2026 following the PRISMA 2020 guidelines. Randomized controlled trials and cohort studies were included, and pooled mean differences (MDs) were calculated using random-effects models. Eight studies involving 1262 participants were analyzed. Linagliptin was associated with a modest reduction in AST (MD −1.58 U/L, 95% CI −2.85 to −0.31) with low heterogeneity, whereas the change in ALT was not statistically significant (MD −1.86 U/L, 95% CI −4.14 to 0.42), and substantial heterogeneity was observed. No significant effects were observed for GGT, while evidence for ALP was limited to a single study and was insufficient to determine the effect of linagliptin. Overall, linagliptin demonstrated limited and inconsistent effects on liver enzyme profiles. Full article

Background/Objectives: Choline is an essential nutrient, and deficiency is associated with metabolic dysfunction-associated steatotic liver disease. Research shows that Western populations have inadequate choline intake; however, the intake in Asian populations is less studied. This study developed a choline database for Thai food and evaluated intake in the Thai population. Methods: Following guidelines of the Food and Agriculture Organization/the International Network of Food Data Systems, 1806 Thai food items were matched to the U.S. choline database, and the missForest imputation method was used to impute missing data. Choline intake was assessed in Thai adults aged 18 years and older using a nationally representative sample of the Thai Food Consumption Survey (n = 3593). Results: Animal-based foods such as eggs, meat, and fish contained more choline than plant-based foods. Median choline intake was 134.7 mg/day (IQR: 70.6, 229.3), with 3.6% of Thai individuals meeting adequate intake levels. Men consumed more choline than women (median 153 vs. 120 mg/day; p < 0.001). Choline intake declined with age but did not differ by body mass index. Conclusions: This study created a choline database for Thai food and shows that most Thais have intake below the recommended intake levels. Full article

Insulin resistance (IR) represents one of the most pressing problems in contemporary public health. Its estimated global prevalence ranges from approximately 15.5% to over 61%, depending on the population studied, the diagnostic criteria applied, and the method used for its assessment. Despite the scale of the problem, IR remains underrecognized and lacks formal definition as a distinct disease entity, even as a growing number of clinicians and researchers worldwide describe it as such. Its asymptomatic or mildly symptomatic course allows it to remain undetected for years, during which it makes a significant contribution to the development of type 2 diabetes, cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), and has been increasingly linked to cellular senescence, certain cancers, neuropsychiatric disorders, and other metabolic conditions. The aim of this review was to summarize current knowledge on the pathophysiology, diagnosis, and clinical implications of insulin resistance, to discuss current challenges in its diagnosis, and to evaluate whether available scientific evidence supports its recognition as a distinct disease entity. This narrative review is based on clinical, epidemiological, and mechanistic data retrieved from PubMed and Google Scholar. Meta-analyses, systematic reviews, clinical and observational studies, clinical guidelines, and expert position statements were analyzed. Animal studies were excluded to maintain a focus on human public health implications. The diagnostic gold standard—the hyperinsulinemic-euglycemic clamp—was discussed, along with surrogate methods used in clinical practice (HOMA-IR, OGTT with insulin measurements, the TyG index, and the TG/HDL-C ratio). Factors potentially contributing to the pathogenesis of IR were examined, including hyperinsulinemia (HI), high-carbohydrate diets, inflammation, stress, and sleep disturbances, as well as conditions in which IR occurs physiologically. The findings indicate that current evidence supports the need for a clearer clinical and diagnostic framework for insulin resistance and suggest that its recognition as a distinct disease entity could facilitate earlier diagnosis, improve the standardization of clinical management, and enable earlier metabolic intervention. Given the steadily rising prevalence of metabolic disease, systemic efforts directed at the early identification and treatment of IR may be a key component of strategies aimed at reducing the population-level burden of metabolic disease and its negative consequences. Full article

Background: Short-term variation in the Fibrosis-4 index (FIB-4) may identify people who warrant further liver assessment. We evaluated longitudinal FIB-4 changes and associated metabolic factors in people with HIV (PWH) and metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: This retrospective cohort included 683 PWH with ultrasound-defined MASLD who underwent routine clinical and laboratory assessments approximately every three months. A prespecified FIB-4 increase required both a ≥20% rise and crossing to ≥1.3 among participants with baseline FIB-4 < 1.3, or a ≥20% rise among those with baseline FIB-4 ≥ 1.3. Results: Of 683 enrolled participants, 655 were analyzed longitudinally. Over a median follow-up of 12.0 months, 59 (9.0%) met the FIB-4 increase definition, corresponding to 8.8 events per 100 person-years. Weight gain was associated with this outcome (adjusted hazard ratio 1.19 per 1% increase, 95% CI 1.14–1.24), whereas HIV- and antiretroviral therapy-related variables were not. Transition from non-obesity to obesity was associated with the outcome (odds ratio 8.45, 95% CI 3.57–20.02). Weight change also correlated with concurrent changes in total cholesterol, triglycerides, fasting glucose, and liver enzymes (all p < 0.01). Conclusions: Weight gain was associated with short-term FIB-4 increase and with concurrent metabolic change in PWH with MASLD. Full article

Background/Objectives: At-risk metabolic dysfunction-associated steatohepatitis (MASH) is associated with increased risks of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Because impaired efferocytosis contributes to persistent hepatic inflammation and fibrotic remodeling in MASH, we investigated whether efferocytosis-associated molecular signatures could identify at-risk MASH. Methods: Bulk RNA-sequencing datasets from Gene Expression Omnibus (GSE135251 and GSE174478) were analyzed to identify differentially expressed efferocytosis-related genes and characterize associated pathways and immune infiltration patterns. Machine learning-based feature selection was used to identify hub genes, which were incorporated into a transcriptomic nomogram. Experimental validation involved reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting of liver tissues from a Western diet-induced murine metabolic dysfunction-associated steatotic liver disease (MASLD) model. Plasma proteomic data were analyzed to explore the discriminatory performance of hub gene products. Results: A total of 17 efferocytosis-related genes (ERGs) associated with at-risk MASH were identified and enriched in pathways related to efferocytosis, inflammation, and immune regulation. Five hub genes, CD24, CHI3L1, TREM2, PTGS2, and LGR6, were shared by all three feature-selection approaches and significantly upregulated in at-risk MASH. A transcriptomic nomogram yielded area under the curve (AUC) values of 0.866 and 0.805 in the training and external cohorts, respectively. In the murine MASLD model, all five hub genes showed increased mRNA and protein expression in advanced disease. Exploratory plasma proteomic analysis identified elevated circulating TREM2 and CHI3L1 levels in at-risk MASH, and a simplified plasma-based model achieved an AUC of 0.736. Conclusions: This study identified a five-gene efferocytosis-associated signature and developed models for identifying at-risk MASH, suggesting that these genes warrant further evaluation as candidate biomarkers. Full article

Pediatric obesity is a complex, multifactorial pandemic with serious early-onset comorbidities, including prediabetes, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular disorders. While lifestyle modifications and the Mediterranean diet remain primary interventions, artificial intelligence (AI) is emerging as a critical tool for early diagnosis and personalized management. This review evaluates the current role of AI in predicting and treating childhood obesity and its complications. A literature search was conducted on PubMed and Google Scholar for English-language articles published from 2015 onward. Search terms included combinations of keywords related to “obesity”, “pediatric”, “comorbidities” (e.g., MASLD, diabetes), and “artificial intelligence” (e.g., machine learning, deep learning, multi-omics). Eligible study types ranged from original articles to systematic reviews and clinical guidelines. By integrating multi-omic data (genome, epigenome, transcriptome, metabolome, microbiota) with socio-psychological metrics, AI can predict obesity risk and early complications. Machine learning (ML) and deep learning have successfully identified specific metabolites, gut flora alterations, neurological pathways, and metabolic SNPs linked to obesity susceptibility. Furthermore, ML-driven prognostic models enable risk assessment for MASLD or diabetes progression, while specialized software supports remote lifestyle monitoring and tailored dietary interventions. AI has the potential to revolutionize pediatric obesity management through precision medicine. However, challenges regarding data privacy, digital literacy, and equitable access persist. Because current evidence relies heavily on limited and heterogeneous pediatric datasets, large-scale, well-characterized, and externally validated cohorts are essential to establish the clinical applicability of AI models before routine implementation. Full article

Chronic liver diseases impose a considerable global public health burden, yet available treatment options remain largely inadequate. The gut microbiota exerts a key modulatory effect on liver disease pathogenesis via the gut-liver axis. Among them, Lachnospiraceae, a dominant bacterial family in the healthy adult gut, has drawn growing interest in recent years. Lachnospiraceae exert protective functions by producing short-chain fatty acids, participating in secondary bile acid conversion, and synthesizing active metabolites such as N-acetyl-glutamic acid, thereby maintaining intestinal barrier integrity and regulating host metabolic and immune homeostasis. Extensive evidence indicates that in cirrhosis, alcohol-associated liver disease, and metabolic dysfunction-associated steatotic liver disease, Lachnospiraceae abundance is consistently and significantly reduced, and this decrease is closely correlated with disease severity and adverse prognosis. In hepatocellular carcinoma, however, different members of Lachnospiraceae exhibit functional divergence, with some butyrate-producing genera decreasing while other subgroups may become enriched and influence the tumor immune microenvironment. Live biotherapeutic products based on Lachnospiraceae have achieved clinical breakthroughs in recurrent Clostridioides difficile infection and metabolic syndrome, providing important references for their translational application in liver diseases. This review systematically synthesizes the abundance changes and mechanisms of Lachnospiraceae across major liver diseases, evaluates their biomarker and therapeutic target potential, and seeks to provide fresh perspectives for precision microbiome-modulating strategies in chronic liver disease management. Full article

Coffee is one of the most widely consumed beverages worldwide. Coffee and its bioactive compounds, including caffeine, chlorogenic acid, and caffeic acid, have attracted increasing attention because of their potential health benefits. Evidence from pediatric and adult populations supports a positive association between fructose intake from sugar-sweetened beverages and the increasing prevalence of obesity and other non-communicable diseases. In this context, coffee consumption may represent a potential protective dietary factor against high fructose intake-induced metabolic alterations, including obesity, type 2 diabetes, liver disease, cardiovascular disease, and alterations in gut microbiota composition. Therefore, this review summarizes current evidence on the potential role of coffee consumption and coffee-derived bioactive compounds in modulating fructose-induced metabolic alterations and discusses the mechanisms involved. However, current evidence from human studies remains limited, and the clinical relevance of the beneficial effects observed in experimental models requires confirmation through well-designed clinical trials. Full article

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors comprising three isoforms—PPARα, PPARγ, and PPARβ/δ—that regulate hepatic lipid metabolism, glucose homeostasis, inflammation, bile acid synthesis, and fibrogenesis. Because liver diseases involve overlapping metabolic, inflammatory, cholestatic, and fibrotic pathways, PPAR agonists have emerged as a versatile therapeutic class across a spectrum of hepatic conditions. PPARα agonists (e.g., fenofibrate) promote fatty acid β-oxidation and suppress de novo lipogenesis; PPARγ agonists (e.g., pioglitazone) improve insulin sensitivity and exert anti-inflammatory and antifibrotic effects; and PPARδ agonists (e.g., seladelpar) regulate bile acid and cholesterol metabolism. Dual agonists (elafibranor [PPARα/δ] and saroglitazar [PPARα/γ]) and pan-PPAR agonists (lanifibranor [PPARα/γ/δ] and bezafibrate) aim to simultaneously address multiple pathogenic mechanisms. In primary biliary cholangitis (PBC), elafibranor and seladelpar received accelerated FDA approval in 2024 based on phase 3 trials (ELATIVE and RESPONSE, respectively), demonstrating significant biochemical response rates of 51% and 62% versus 4% and 20% with the placebo. Long-term open-label extension data from the ELATIVE trial have demonstrated sustained improvements in cholestatic biomarkers and stabilization of fibrosis markers over three years, with durable benefits on fatigue and pruritus. The ASSURE open-label study has confirmed the durability of seladelpar’s effects on biochemical response and pruritus through up to two years of treatment. Saroglitazar, a dual PPARα/γ agonist, has shown positive topline phase 3 results in the EPICS-III trial and received an FDA priority review designation. Bezafibrate has shown a survival benefit in large retrospective analyses and is used as a second-line therapy in Europe and Japan; notably, bezafibrate functions as a dual PPAR/pregnane X receptor (PXR) agonist, inducing CYP3A4 and efflux transporters that contribute to bile acid detoxification. In metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), pioglitazone remains the most extensively studied PPAR agonist, with meta-analytic evidence supporting MASH resolution and fibrosis reduction regardless of diabetes status. Lanifibranor demonstrated histological improvement in the phase 2b NATIVE trial and is currently in phase 3 development (NATiV3). PPAR agonists have also demonstrated therapeutic effects on liver fibrosis inhibition through direct modulation of hepatic stellate cell activation and suppression of fibrogenic signaling. This narrative review synthesizes the molecular pharmacology of PPAR isoforms; the available clinical and preclinical evidence for mono-, dual-, and pan-PPAR agonists; and their therapeutic applications across MASLD/MASH, alcohol-associated liver disease (ALD), PBC, primary sclerosing cholangitis (PSC), intestinal failure-associated liver disease (IFALD), and advanced chronic liver disease (ACLD). The evolution from single-isoform to multi-isoform PPAR agonism reflects the recognition that overlapping pathogenic mechanisms in liver diseases may require broader receptor coverage for optimal therapeutic efficacy. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are a growing global health burden with extremely limited pharmacological options, thereby indicating an urgent need for innovative therapeutic strategies. Hepatokines are liver-derived secreted proteins that coordinate metabolic communication between the liver and peripheral organs and have emerged as mechanistically compelling therapeutic candidates. This review comprehensively examines beneficial hepatokines with protective roles in MASLD/MASH, detailing their molecular mechanisms of action across key metabolic tissues, including their effects on hepatic lipid metabolism, insulin sensitivity, inflammatory signaling, and fibrogenesis. We further discuss the fundamental pharmacokinetic barriers of these protein therapeutics, particularly their susceptibility to renal clearance and proteolytic degradation. Furthermore, we examine the principal half-life extension strategies to overcome these limitations, with particular emphasis on their clinical application to FGF21-based drug candidates that are currently advancing through phase 3 trials. Overall, this review highlights the therapeutic potential of hepatokine-based biologics and the critical role of protein engineering in translating these mechanistic insights into durable, clinically viable treatments for MASLD/MASH. Full article

Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with substantial morbidity, and hepatic fibrosis stage is the strongest predictor of long-term outcomes. Although liver biopsy remains the reference standard for fibrosis assessment, its invasiveness has driven the development of noninvasive diagnostic tools, including transient elastography (TE) and serum-based fibrosis scores. To evaluate and compare the diagnostic performance of TE and commonly used serum-based fibrosis scores for detecting clinically significant fibrosis (≥F2) in patients with biopsy-proven MASLD. Materials and Methods: This retrospective cross-sectional exploratory diagnostic accuracy study included 30 adults with biopsy-confirmed MASLD. Patients were classified into clinically significant fibrosis (CSF, ≥F2; n = 9) and no/mild fibrosis (NMF, F0–F1; n = 21) groups. Among the nine patients with CSF, six had stage F2 fibrosis and three had stage F3 fibrosis. TE, FIB-4, APRI, NAFLD Fibrosis Score (NFS), BARD score, and HOMA-IR were evaluated. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis, optimal cutoff values, dual-cutoff strategies, and confusion matrix analysis. Results: TE, FIB-4, and APRI demonstrated the highest diagnostic performance (AUROC: 0.93 for each). TE showed the most balanced diagnostic accuracy (sensitivity 88.9%, specificity 90.5%), whereas APRI provided the highest specificity (95.2%) and the strongest positive likelihood ratio (+LR: 18.67). FIB-4 achieved 100% sensitivity with lower specificity (76.2%). NFS demonstrated moderate diagnostic performance (AUROC: 0.83) with a relatively wide gray zone (56.7%), whereas BARD and HOMA-IR showed limited discriminative ability. When fibrosis categories automatically assigned by the TE device were evaluated, the overall diagnostic accuracy was 93.3%. Conclusions: TE, FIB-4, and APRI demonstrated promising diagnostic performance as noninvasive tools for identifying clinically significant fibrosis in biopsy-proven MASLD. These findings generate the hypothesis that a sequential diagnostic strategy using serum-based fibrosis scores for initial risk stratification followed by TE for confirmation may reduce the need for liver biopsy. However, this hypothesis requires confirmation in larger prospective validation studies. Full article