Search Results (212)

The global burden of type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise at an alarming pace, with substantial pathophysiological overlap driven by insulin resistance, visceral obesity, and chronic low-grade inflammation. MASLD may progress to metabolic dysfunction-associated steatohepatitis (MASH), with increased risk of cirrhosis and hepatocellular carcinoma. Glucagon-like peptide 1 (GLP-1)-based therapies have transformed the management of T2DM and obesity. They exert pleiotropic effects whose basis remains incompletely understood. Concurrently, Akkermansia muciniphila has emerged as a keystone gut microbiota species with demonstrated hepatoprotective potential in preclinical models of MASLD/MASH. This narrative review positions A. muciniphila simultaneously as a target of GLP-1-mediated microbiome remodeling and as an independent modulator of hepatoprotection in MASLD/MASH. A structured search of PubMed, Scopus, and Web of Science (last searched: 12 April 2026) was conducted using terms related to Akkermansia muciniphila, GLP-1 receptor agonists, MASLD/MASH and T2DM. A total of 174 records were identified. Of these, 148 were excluded due to duplication or non-relevant study design. 26 studies (23 preclinical, 3 clinical) were included in the synthesis, directly addressing A. muciniphila. Preclinical evidence demonstrates that liraglutide, semaglutide, exenatide, and tirzepatide increase A. muciniphila abundance, while A. muciniphila in turn enhances endogenous GLP-1 secretion via the P9/ICAM-2 axis, forming a hypothetical positive feedback loop. A working mechanistic model integrating these bidirectional interactions is proposed, alongside a discussion of current limitations and future research priorities, including microbiome-guided clinical trials in MASLD/MASH populations. Full article

Circulating sex hormone-binding globulin (SHBG) concentrations are lower in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), reflecting its potential role in metabolic liver dysfunction. Our prior studies demonstrated that SHBG can attenuate MASLD by limiting hepatic lipid deposition, partly through suppression of lipogenic pathways, in both cellular and animal models. In the present work, we have examined whether SHBG could protect against development of liver fibrosis. For this purpose, in vitro and in vivo studies were performed. In vitro, we used co-cultures of human hepatocellular carcinoma cell line (HepG2) and human hepatic stellate cell line (LX-2) cells transfected using an SHBG expression vector vs. vehicle and treated with transforming growth factor beta 1 (TGF-β1). For in vivo studies we used wild-type and human SHBG transgenic mice developing liver fibrosis induced by carbon tetrachloride (CCl₄). Our results clearly showed that SHBG overexpression reduced the TGF-β1-induced expression in collagen in LX-2 cells. Moreover, SHBG overexpression reduced the CCl₄ induced liver fibrosis in both male and female mice. Histological examination revealed that SHBG transgenic mice had reduced NAS score and decreased collagen accumulation, assessed by Sirious Red staining. In addition, human SHBG transgenic mice treated with CCl₄ exhibited lower collagen 1A1 (Col1A1) protein levels when compared with wild-type CCl₄ treated mice. Mechanistically, SHBG attenuated fibrosis primarily through modulation of the TGF-β1/matrix metalloproteinases (MMPs)/tissue inhibitor metalloproteinases 1 (TIMP1) axis, characterized by reduced TGF-β1 levels, increased metalloprotease activity, and decreased TIMP1 levels compared with wild-type CCl₄ treated mice. Notably, female SHBG transgenic mice exhibited greater protection against fibrosis than males, indicating a sex-dependent effect likely mediated by differences in sex steroid signaling. Taken together, we demonstrate for the first time that SHBG protects against liver fibrosis by promoting collagen degradation via the TGF-β1/MMPs/TIMP1 pathway. Further research is needed to elucidate the role of sex steroids in the regulation of MMPs and the observed sexual dimorphism. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now recognized as the principal hepatic manifestation of obesity and metabolic dysfunction. Its pathogenesis is complex and multifactorial, driven by insulin resistance, low-grade chronic inflammation, oxidative stress, gut microbiota alterations, and abnormalities in lipid metabolism; together, these promote steatosis, lipotoxicity, and progression to fibrosis which can lead to compensated advanced chronic liver disease (cACLD). MASLD is also a multisystem condition closely associated with an increased risk of major adverse cardiovascular events such as myocardial infarction, ischemic stroke, atrial fibrillation, and other extrahepatic complications. In this context, emerging metabolic therapies show significant potential for modifying the natural history of the disease. Glucagon-like peptide (GLP)-1 receptor agonists induce substantial weight loss and improve steatosis and necro-inflammatory activity. Sodium–glucose cotransporter 2 inhibitors (SGLT-2I) reduce glucotoxicity, promote modest weight loss, and lower hepatic fat content by improving insulin sensitivity and inflammatory signaling. Even more promising are dual GLP-1/GIP receptor agonists, which have demonstrated superior efficacy in metabolic control, reducing hepatic steatosis, and potentially modulating fibrotic processes, although definitive histological confirmation is still lacking. Overall, in this review, we discuss the physiopathological mechanisms of MASLD leading to cACLD along with the emerging therapies, such GLP1 receptor agonists, SGLT-2I, and GLP1/GIP which, when combined with structured lifestyle interventions, may attenuate progression toward steatohepatitis (MASH), fibrosis, and, thus, cirrhosis. Full article

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver disease worldwide, affecting approximately 25% of the global population. MAFLD represents a broad disease spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The availability of experimental models that faithfully reproduce human metabolic and hepatic pathology is essential for elucidating disease mechanisms and advancing therapeutic development. This review aims to critically evaluate commonly used rodent models of MAFLD and provide guidance for model selection based on specific research objectives. Methods: A narrative, semi-systematic literature search was performed using PubMed Central, Ovid MEDLINE, and Google Scholar. Rodent models were classified according to their mode of disease induction, including diet-induced, genetically engineered, chemically or pharmacologically induced, and combination models. Models were assessed based on frequency of use, relevance to different stages of MAFLD progression, metabolic fidelity, and suitability for mechanistic studies and preclinical therapeutic evaluation. Results: Diet-induced models incorporating high fat, fructose, and cholesterol most closely recapitulate human metabolic dysfunction and are highly relevant for translational research and drug screening. Nutrient-deficient diets induce rapid steatohepatitis and fibrosis but lack key features of metabolic syndrome. Genetic models enable the targeted interrogation of specific metabolic and inflammatory pathways, whereas chemical and combination models accelerate fibrosis and HCC development. No single rodent model fully reproduces the entire spectrum of human MAFLD. Conclusions: Rodent models remain indispensable tools for MAFLD research; however, their applicability depends on alignment with the defined experimental goals. Careful selection of models based on disease stage, dominant pathogenic mechanisms, and translational intent is essential for improving reproducibility and clinical relevance. This review provides a practical framework to guide investigators in choosing appropriate preclinical models for mechanistic studies and therapeutic development in MAFLD. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of global chronic liver disease, with a prevalence of approximately 30%. This review outlines the diagnostic transition from the exclusionary non-alcoholic fatty liver disease (NAFLD) framework to the affirmative MASLD nomenclature, which mandates the presence of at least one of five specific cardiometabolic risk factors (CMRFs) to prioritize active pathophysiology. Beyond hepatic complications, MASLD drives systemic metabolic failure, significantly elevating risks for type 2 diabetes, hepatocellular carcinoma, and cardiovascular disease, the primary cause of mortality in this cohort. Clinical management relies on a standardized, two-tier risk-stratification pathway for advanced fibrosis. Primary care triage utilizes the Fibrosis–4 (FIB–4) index; a score < 1.3 excludes advanced disease via a high negative predictive value, whereas indeterminate or high scores require secondary validation via vibration-controlled transient elastography (VCTE) or the enhanced liver fibrosis (ELF) test to guide specialist referral. Although lifestyle modifications, principally a 7–10% weight reduction and Mediterranean diet adherence, remain foundational, management has transitioned toward disease-modifying pharmacotherapies. A pivotal breakthrough occurred with the 2024 FDA approval of resmetirom, a selective thyroid hormone receptor-beta (THR-β) agonist, for non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-advanced fibrosis. Concurrently, the emergence of GLP-1 receptor agonists and multi-incretin mimetics offers a personalized, multi-target approach simultaneously addressing hepatic inflammation, glycemic control, and adiposity. Full article

Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH) is frequently accompanied by disturbances in coagulation and metabolic homeostasis, partly related to impaired handling of vitamin K-dependent pathways. Although vitamin K is often administered to correct abnormal coagulation tests, its biochemical impact in hospitalized patients with MASH remains insufficiently characterized. This study aimed to evaluate changes in coagulation and metabolic parameters in hospitalized patients with MASH receiving vitamin K supplementation. Methods: We conducted a retrospective study of 84 hospitalized MASH patients who received vitamin K supplementation. Biochemical parameters were recorded at admission and discharge to assess short-term changes during hospitalization. Results: Vitamin K supplementation was associated with modest changes in coagulation parameters, including reductions in PT, INR, and aPTT (e.g., PT decreased from 13.00 s to 11.00 s). Small numerical changes in transaminases, fasting glucose, and total cholesterol were observed during hospitalization, with limited clinical relevance. These patterns were comparable across fibrosis stages, with no significant differences between groups. Discussion: The observed biochemical findings are likely in-hospital factors rather than a direct metabolic effect of vitamin K. Conclusions: Vitamin K supplementation was associated with modest changes in coagulation parameters and small, clinically negligible variations in selected metabolic markers in patients with MASH, irrespective of fibrosis stage. These findings suggest a supportive biochemical effect in selected contexts; further prospective studies are needed to clarify their clinical relevance. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has replaced older exclusion-based terminology as the preferred term for steatotic liver disease associated with cardiometabolic risk factors. MASLD is now among the most common causes of chronic liver disease and may progress from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. This updated rigorous narrative review synthesizes current evidence on MASLD diagnosis and management, with emphasis on the gut–liver axis and the therapeutic potential of combining probiotics with metformin. A structured narrative search was conducted in PubMed, PMC, ScienceDirect, Taylor & Francis, Cochrane Library, and Google Scholar using the keywords “MASLD”, “MAFLD”, “NAFLD”, “MASH”, “probiotics”, “synbiotics”, “metformin”, and “gut-liver axis”. The review was designed as a narrative synthesis rather than a systematic review. Current guidance supports stepwise risk stratification using serum fibrosis scores followed by elastography or advanced imaging when indicated. Ultrasonography remains accessible but has limited sensitivity for mild steatosis, is operator-dependent, and is not sufficient for comprehensive assessment of fibrosis or disease activity. Metformin is appropriate for type 2 diabetes mellitus and improves insulin resistance, but current guidelines do not recommend it as a targeted treatment for MASH because histological benefit has not been consistently demonstrated. Probiotics and synbiotics may improve aminotransferases, inflammatory markers, lipid parameters, intestinal barrier function, and gut dysbiosis; however, findings vary by strain, formulation, dose, treatment duration, population, and endpoint. The combination of probiotics and metformin is mechanistically plausible because it targets both metabolic dysfunction and intestinal dysbiosis, but human evidence remains limited. Larger, strain-specific, adequately powered trials using standardized MASLD criteria and clinically meaningful endpoints are required before routine clinical recommendations. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as key drivers of hepatocellular carcinoma (HCC). Unlike HCC caused by viral infections or alcohol, MASLD/MASH-related liver cancer develops within a chronic immunometabolic environment characterized by lipotoxicity, sterile inflammation, fibrogenesis, and remodeling of the microenvironment. In this setting, interleukin-10 (IL-10) has attracted growing attention due to its complex, context-dependent roles in immune regulation and tumor immune tolerance. This review explores IL-10 biology and its connection to MASLD/MASH-associated HCC, emphasizing the paradox that IL-10 may diminish harmful inflammation in early stages while promoting immunosuppressive conditions in advanced disease. To supplement existing research, we performed an exploratory reanalysis of publicly available bulk liver RNA-seq data from a mouse model that progresses from MASLD/MASH to HCC. The reanalysis revealed a receptor- and effector-specific rewiring of the IL-10 pathway: while the expression of canonical signaling genes (Stat3, Jak1, Jak2, Tyk2, Socs3) showed minimal changes across stages, receptor subunits (Il10ra, Il10rb) and IL-10-responsive effectors (such as Scd2, related to lipid metabolism, and Ddit4, involved in mTOR and glycolysis regulation) displayed strong stage-dependent induction. This was accompanied by a decrease in hepatocyte signature profiles and an increase in stromal and immune signatures. These results generate new hypotheses and raise key questions—particularly whether a large portion of IL-10 modulation originates from peripheral or non-parenchymal sources, and whether the transcriptional patterns observed reflect protein-level changes—that will require stage-specific, cell-focused human studies incorporating proteomic and cytokine measurements. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent global health concern driven by metabolic imbalance and excess caloric intake, leading to hepatic steatosis, inflammation, and fibrosis that may progress to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, or hepatocellular carcinoma. Current management relies primarily on lifestyle interventions and, in advanced stages, pharmacological therapies; however, long-term outcomes remain limited due to variable efficacy and poor sustainability. Recent advances in pharmacotherapy, including GLP-1 receptor agonists, THR-β agonists and SGLT2 inhibitors, have shown clinically meaningful improvements in metabolic parameters and hepatic steatosis, although their impact on fibrosis and long-term disease modification remains uncertain. In parallel, genomic and nanotechnology-based strategies (such as RNA-based therapies and nanoparticle delivery systems) have emerged as promising approaches to enhance drug stability, targeting, and therapeutic precision. Despite these advances, most emerging strategies remain at preclinical or early translational stages, with significant challenges related to safety, scalability, regulatory approval, and long-term efficacy. In this context, this review provides an integrative synthesis of pharmacological, genomic, and nanotechnology-based therapies, highlighting their mechanisms, limitations, and translational potential. Future research should focus on well-designed clinical trials, standardized evaluation frameworks, and the development of personalized therapeutic approaches. The convergence of these strategies may enable more effective and durable interventions for MASLD. Full article

The recent redefinition of steatotic liver diseases, introducing metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), reflects a growing consensus among liver societies and marks a paradigm shift in disease classification. MASLD subsumes former categories of nonalcoholic fatty liver disease (NAFLD) and incorporates metabolic criteria alongside moderate alcohol intake, while MASH replaces nonalcoholic steatohepatitis (NASH), aligning terminology with disease mechanisms. This evolution clarifies the diagnostic criteria and minimizes stigma, facilitating more consistent epidemiological and clinical investigations. Recent advances in noninvasive diagnostics, including vibration-controlled transient elastography, magnetic resonance elastography, shear-wave elastography, and the Enhanced Liver Fibrosis test, have improved the identification and stratification of patients with advanced fibrosis. Current guidelines recommend targeted screening in populations at elevated metabolic risk, enabling earlier intervention and personalized management. Population studies indicate that MASLD affects over one-third of adults and is a major contributor to cardiovascular and metabolic morbidity. Therapeutic progress is highlighted by the approval of novel agents such as resmetirom and semaglutide for the treatment of MASH with fibrosis. Emerging dual and triple agonists, as well as sodium–glucose cotransporter inhibitors, offer additional promise, although further research is required to define their long-term efficacy and safety. As the disease prevalence escalates globally, the integration of multidisciplinary care, the ongoing refinement of diagnostic tools, and the expansion of therapeutic options will remain essential to optimizing outcomes for affected individuals. Full article

Background/Objectives: It is estimated that one in three adults in the US has one or more risk factors for cardiovascular–kidney–metabolic (CKM) syndrome. The American Heart Association (AHA) has warned that the interaction between obesity, Type 2 diabetes (T2D), chronic kidney disease (CKD), and cardiovascular disease (CVD) leads to a multistage CKM syndrome with elevated mortality. This narrative review describes the newly coined terms CKM health and CKM syndrome, introduced by the AHA Presidential Advisory in 2023. Methods: In this narrative review, we will discuss the epidemiology and development of CKM syndrome, CKM stages, and the possible impact of precision nutrition on CKM and evaluate what is currently known about the role of nutrient metabolism in the physiological state and pathogenesis of CKM. Results: Since the AHA defined CKM syndrome in 2023, several studies have analyzed NHANES data to identify the correlations between CKM stages and adverse health outcomes. Studies also found that correlations between dietary intake and diet patterns may contribute to the protection against progression through various stages of CKM. However, experimental research and clinical studies are still lagging. Although the liver plays an integral role in nutrient metabolism, energy homeostasis, protein synthesis, nutrient storage, antibody production, and detoxifying compounds, it has not been included in the definition of CKM. Conclusions: Integrated body systems contribute to the development and progression of CKM. Precision nutrition and dietary patterns may play a role in the management of CKM and related comorbidities. Further research is warranted to address the role of precision nutrition in the prevention, early detection, and intervention in CKM syndrome as part of a comprehensive approach. It would be worth considering including metabolic dysfunction-associated liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) within the CKM framework. Full article

Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe hepatic steatosis, lobular inflammation, and fibrosis. Although hesperidin, a citrus-derived flavanone, has been reported to exert metabolic and anti-inflammatory effects, its role in severe inflammatory and fibrotic conditions such as MASH remains incompletely understood. This study aimed to evaluate the effects of hesperidin in MASH using integrated in silico and in vivo approaches. Methods: Potential targets of hesperidin were identified using network pharmacology and molecular docking. For in vivo validation, C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for five weeks, with oral administration of hesperidin (150 or 300 mg/kg/day) starting from week two. The MCD model induces severe hepatic inflammation and fibrosis but does not fully reflect metabolic features such as obesity and insulin resistance. Hepatic histology, serum transaminases, immune cell populations, and hypothalamic neuroinflammatory markers were assessed. Results: In silico analyses suggested that hesperidin interacts with key regulators associated with MASH, including PPARG, TGFB1, and TNF. In the in vivo MCD-induced model, hesperidin treatment reduced hepatic lipid accumulation and collagen deposition, accompanied by significant decreases in serum ALT and AST levels (by approximately 30–34% and 42–53%, respectively, depending on dose). These effects were associated with downregulation of pro-inflammatory and pro-fibrogenic gene expression and increased expression of antioxidant markers. In addition, hesperidin decreased circulating Ly6C^high monocytes and hepatic Kupffer cells, along with reduced hypothalamic microglial and astrocyte activation. Conclusions: Hesperidin attenuated key pathological features of MASH, including steatosis, inflammation, and fibrosis, and was associated with modulation of peripheral immune responses and central neuroinflammatory markers. These findings suggest that hesperidin may influence the liver–immune–brain axis and warrant further investigation in models that more closely reflect human metabolic conditions. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive stage of metabolic dysfunction-associated steatotic liver disease characterized by lipid dysregulation, oxidative stress, inflammation, and fibrosis. Because these processes occur simultaneously, compounds targeting multiple pathways may offer therapeutic benefit. Naringin, a citrus-derived flavonoid, has reported antioxidant and anti-inflammatory properties, but its integrated effects in MASH remain unclear. In this study, the effects of naringin were evaluated using combined in silico analysis and in vivo experiments. Network pharmacology and molecular docking predicted targets related to lipid metabolism, oxidative stress, inflammation, and fibrosis, which were validated in a methionine- and choline-deficient diet-induced mouse model. Naringin reduced hepatic lipid accumulation and improved serum AST and ALT levels. It modulated oxidative stress-related genes, attenuated inflammatory responses, and reduced fibrogenic markers. Naringin also decreased Ly6Chigh inflammatory monocytes and Kupffer cell activation, and reduced hypothalamic microglial activation. These findings suggest that naringin exerts multi-target effects across hepatic, systemic, and central pathways, supporting its potential as a therapeutic candidate for MASH. Full article

Background/Objectives: Chronic liver diseases, including metabolic dysfunction-associated steatohepatitis (MASH) and chronic viral hepatitis (CVH), are major global health concerns due to their potential progression to cirrhosis, liver failure, and hepatocellular carcinoma. Because liver biopsy, despite meeting the diagnostic gold standard, is invasive and associated with complications, non-invasive fibrosis assessment tools have been increasingly recommended in clinical practice. This study aimed to compare the diagnostic performance of several non-invasive fibrosis markers (ARR, APRI, FI, FIB-4, API, NFS, BARD) and transient elastography in detecting advanced liver fibrosis (F4) in patients with MASH and CVH. Methods: This retrospective study included 237 adult patients (77 MASH, 160 CVH) who underwent liver biopsy between 2017 and 2025 at the University Clinical Center of Serbia. CVH included chronic hepatitis B (CHB) and C (CHC). Patients were evaluated using serum fibrosis indices and TE, and results were compared to histological staging (F0–F4). ROC analysis assessed diagnostic performance. Results: Cirrhosis (F4) was more common in CVH than MASH (p < 0.001). In MASH, NFS (AUROC 0.931), FIB-4 (0.915), BARD (0.872), and APRI (0.878) showed high diagnostic accuracy for F4. In CHC, APRI (0.931), FIB-4 (0.863), and TE (0.938) had strong performance, while in CHB, TE (0.987) outperformed FIB-4 (0.821). Sensitivity and specificity varied by test and cohort, with TE consistently yielding the best results where available. Conclusions: Non-invasive methods, particularly NFS and FIB-4 for MASH and TE for CVH, effectively identify advanced fibrosis. Their application could significantly reduce the need for biopsy, especially in high-risk groups. TE demonstrated superior accuracy, but access limitations highlight the continued relevance of serum-based scores. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and a major contributor to the global cardiometabolic burden. Early identification of patients at risk of metabolic dysfunction-associated steatohepatitis (MASH) and advanced fibrosis is essential to prevent liver-related and cardiovascular complications. In Spain, the burden of MASLD is increasing, yet information on routine clinical management by gastroenterologists remains limited. Methods: A nationwide cross-sectional online survey was conducted among members of the Spanish Society of Digestive Diseases (SEPD). The questionnaire explored five domains: MASLD knowledge, use of non-invasive biomarkers and imaging, awareness and implementation of clinical guidelines, cardiometabolic and alcohol-related risk assessment, and coordination with primary care. Results: A total of 429 specialists responded, 33.1% reported more than 20 years of practice and most worked in public hospitals, including 29.2% in large tertiary centers. Awareness of the MASLD definition was high, and 91.2% identified fibrosis as the main prognostic determinant. Non-invasive fibrosis biomarkers were widely used, whereas steatosis biomarkers were less frequently applied. Elastography was available to 96.1%. Guideline knowledge was reported by 80.4%, although implementation was lower. Cardiovascular risk evaluation varied: 75.1% reported systematic screening. Alcohol consumption was usually assessed. Coordination with primary care was limited: 91.1% expressed concerns regarding physicians’ familiarity with MASLD classification, and only 31.1% reported shared protocols. Conclusions: Spanish gastroenterologists show high awareness of MASLD and broad access to non-invasive diagnostic tools. However, important gaps remain in cardiovascular and alcohol risk assessment, guideline implementation, and coordination with primary care. Full article