Search Results (3,460)

Metabolic dysfunction-associated steatohepatitis (MASH; formerly non-alcoholic steatohepatitis, NASH) is characterized by oxidative stress, inflammatory activation, hepatocellular injury, and progressive liver dysfunction. However, the global transcriptomic landscape underlying stress-induced hepatic injury remains incompletely understood. In this study, we employed a methionine–choline-deficient (MCD) diet-induced murine model to characterize the phenotypic and transcriptomic alterations associated with liver injury. Male C57BL/6J mice were fed either a control or MCD diet, and hepatotoxicity was assessed by survival analysis, body and liver weight measurements, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, histopathological examination, RNA sequencing, quantitative real-time PCR (qRT-PCR), and tumor necrosis factor-alpha (TNF-α) enzyme-linked immunosorbent assay (ELISA). MCD feeding markedly reduced survival and body weight while inducing hepatomegaly and significant elevations in serum ALT and AST, indicating severe hepatocellular injury. Histopathological analysis demonstrated hepatic steatosis, hepatocellular ballooning, and lobular inflammation without histological evidence of fibrosis. Transcriptomic profiling revealed extensive gene expression remodeling, characterized by activation of inflammatory pathways, enrichment of MAPK-related signaling, dysregulation of lipid metabolism, suppression of antioxidant defense systems, impairment of cytochrome P450-mediated detoxification, and upregulation of apoptosis-associated genes. qRT-PCR further validated the differential expression of representative genes involved in inflammatory signaling (Tlr4, Nfkb1, Nlrp3, and Casp1), MAPK signaling (Fos), xenobiotic metabolism (Cyp4f18), lipid metabolism (Apoa4 and Lpl), extracellular matrix remodeling (Mmp12), and oxidative stress responses (Sod1 and Gstp1). In addition, elevated serum TNF-α levels provided protein-level evidence supporting activation of the TLR4/NF-κB/TNF-α/NLRP3 inflammatory axis. Although fibrosis-associated transcriptional responses were detected, the absence of histological fibrosis suggests transcriptional priming of fibrogenic pathways rather than established fibrogenesis. Collectively, these findings provide a transcriptomic framework linking oxidative stress, impaired detoxification, inflammatory activation, and stress-responsive signaling to MCD-induced hepatic injury. The MCD model provides a valuable experimental platform for characterizing hepatic stress-response transcriptomes and for generating hypotheses that can subsequently be evaluated in environmentally relevant toxicological models. Nevertheless, caution should be exercised when extrapolating these findings to obesity-associated human MASLD, as the MCD model lacks key metabolic features of the human disease, including obesity and insulin resistance. Therefore, the present findings should be interpreted primarily as transcriptomic signatures of stress-induced hepatic injury rather than as a direct representation of the pathophysiological processes underlying human obesity-associated MASLD. Full article

Background: Respiratory failure (RF) is a frequently fatal complication of chronic liver disease (CLD), yet population-level data on RF-related mortality trends among adults with CLD are lacking. This study characterized temporal trends and demographic disparities in RF-related mortality among U.S. adults with CLD from 1999 to 2024. Methods: Death certificate data were obtained from the CDC WONDER database for adults aged ≥25 years with both RF (ICD-10: J96) and CLD (ICD-10: K70–K76) listed as an underlying or contributing cause of death. Age-adjusted mortality rates (AAMRs) per 100,000 were calculated using the 2000 U.S. standard population. Joinpoint regression identified temporal inflection points and annual percentage change (APC). Results: Among 241,075 deaths, the overall AAMR increased 3.2-fold from 2.237 (1999) to 7.162 (2021) per 100,000, then declined to 6.132 by 2024. Joinpoint analysis identified four segments: moderate increase (1999–2006; APC +2.40%), accelerated increase (2006–2018; APC +5.37%), late acceleration period (2018–2021; APC +13.10%), and post-pandemic decline (2021–2024; APC −4.32%; all p < 0.001). The 2024 AAMR remained 174.2% above baseline. The male-to-female rate ratio narrowed from 2.02 to 1.50, with females showing steeper acceleration (+14.38% vs. +12.36%). American Indian or Alaska Native individuals had the highest AAMRs and the most dramatic surge (APC +26.90%). Rural areas surpassed urban AAMRs by 2020, with steeper post-2007 acceleration (+8.74% vs. +5.51%). The Western U.S. consistently had the highest regional rates. Younger adults aged 25–34 and 35–44 showed 2.96-fold and 2.37-fold increases in crude mortality rates, respectively. Approximately 80% of deaths occurred in inpatient settings. Conclusions: RF-related mortality among U.S. adults with CLD increased more than threefold from 1999 to 2021, with a dramatic surge followed by incomplete decline. Persistent disparities by sex, race/ethnicity, urbanization, and region highlight the need for targeted interventions, including expanded screening for alcohol-associated and metabolic liver disease and improved access to hepatology services in underserved communities. Full article

Alcohol-related liver disease (ALD) poses a significant global health burden, driven by complex mechanisms including oxidative stress, inflammation, and gut–liver axis disruption. While the individual roles of gut microbiota dysbiosis and ageing in ALD pathogenesis are increasingly recognized, their synergistic interaction remains poorly understood. This review synthesizes current evidence to argue that there is an interaction between ageing and the gut microbiota that collectively amplifies progression of ALD. Specifically, ageing promotes gut dysbiosis through immunosenescence (e.g., reduced IgA diversification and antimicrobial peptide decline), intestinal barrier failure, and altered microbial metabolite profiles (e.g., decreased short-chain fatty acids and dysregulated bile acid metabolism). Conversely, dysbiosis-derived metabolites and endotoxins modulate ageing-related signaling pathways, including SIRT1, FOXO, and Nrf2, thereby accelerating hepatic cellular senescence, inflammation, and fibrogenesis. Furthermore, we also discussed the typical microbial changes in ALD. These include an increase in the Proteobacteria, a decrease in the Bacteroidetes, as well as imbalances in fungi and viruses. In ageing, similar but distinct shifts occur, such as reduced microbial diversity, decreased short-chain fatty acid producers, and increased intestinal permeability. Therapeutic strategies targeting the gut microbiota (probiotics, fecal microbiota transplantation) or ageing-related pathways (SIRT1 activators) hold promise. Future research priorities include validating ageing-associated microbial signatures as predictors of ALD progression and testing microbiota-targeted interventions in aged preclinical models. Collectively, this review identifies the microbiota–ageing axis as a tractable therapeutic target for ALD and provides a framework for future mechanistic and translational studies. Full article

Background: Type 2 diabetes mellitus (T2DM) is associated with subclinical myocardial dysfunction, which may occur despite preserved left ventricular ejection fraction. Left ventricular global longitudinal strain (LV GLS) is a sensitive marker of early systolic impairment and may detect subtle changes in myocardial function before conventional echocardiographic parameters become abnormal. The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on LV GLS in adults with T2DM remains incompletely defined. Objective: To synthesize the available evidence on the effects of SGLT2i therapy on LV GLS or LV strain in adults with T2DM. Methods: Original full-text human studies evaluating SGLT2i therapy in adults with T2DM and reporting LV GLS or LV strain were included. LV GLS was assessed primarily by speckle-tracking echocardiography, while one study used cardiac magnetic resonance feature-tracking. Reviews, conference abstracts, protocols, animal-only studies, and studies without LV strain assessment were excluded. Risk of bias was assessed using RoB 2 for randomized studies and ROBINS-I for non-randomized studies. Results: Twenty-six studies involving more than 2300 participants were included. The studies evaluated dapagliflozin, empagliflozin, ertugliflozin, canagliflozin, or mixed SGLT2i regimens across heterogeneous clinical populations, including patients with preserved ejection fraction, pre-heart failure, diabetes-related cardiomyopathy, chronic heart failure, coronary artery disease, hypertension, non-alcoholic fatty liver disease, and cardio-oncology risk. Most observational and before–after studies reported favorable changes in LV GLS after SGLT2i therapy, whereas randomized and controlled studies showed more variable findings. Several studies also reported improvements in LV remodeling, diastolic function, left atrial function, myocardial work indices, NT-proBNP, cardiometabolic parameters, or epicardial adipose tissue thickness. However, the certainty of evidence was limited by methodological heterogeneity, differences in comparator groups, variable follow-up duration, non-standardized imaging protocols, and risk of bias, particularly in non-randomized and single-arm studies. Conclusions: SGLT2i therapy may be associated with favorable changes in LV GLS in adults with T2DM, suggesting a potential beneficial effect on subclinical left ventricular systolic function. However, current evidence does not definitively establish a consistent treatment effect across all populations. Larger randomized controlled trials with standardized strain imaging protocols, predefined LV GLS endpoints, and clinically relevant follow-up are needed to determine whether SGLT2i-related improvements in LV GLS reflect true myocardial benefit and translate into improved cardiovascular outcomes. Full article

Background: Alcohol-related liver disease (ALD) affects 4.8% of the global population. Among these patients, between 13.4% and 19.6% suffer from alcoholic hepatitis (AH), which, in its severe form, is associated with significant short- and long-term mortality. Current therapeutic options are limited, offering only modest short-term survival benefits. Recent studies suggest that microbiota-based therapies may offer a novel therapeutic opportunity for patients with ALD. Methods: Databases including Embase, Medline, and CENTRAL were searched until 4 February 2026. The pre-registered protocol on PROSPERO (CRD42023467455) was followed without deviation. Studies comparing adult patients with ALD, treated with fecal microbiota transplantation (FMT) or standard of care (SOC), were included. Outcomes investigated included overall survival, alcoholic recidivism, adverse events (AEs), and disease severity scores. Risk of bias (ROB) was assessed using the ROBINS-I and ROB 2 tools. Hazard ratios (HR) were calculated for FMT versus SOC groups. Results: Overall, 10 studies were eligible for inclusion, with 339 patients eligible for synthesis. In these patients, FMT was associated with significantly improved overall survival compared to the SOC, with an HR of 0.50 (95% confidence interval (CI): 0.35–0.72; p = 0.0002). When comparing FMT with pentoxifylline, the HR was 0.45 (95% CI: 0.21–0.96; p = 0.0345), and when FMT was compared with nutritional support alone, the HR was 0.36 (95% CI: 0.19–0.66; p = 0.0001). But FMT did not reach statistical significance when compared to glucocorticoids. ROB analysis showed a moderate to high risk of bias, and the overall certainty of evidence was low. Discussion: FMT is a promising therapeutic option for improving short- and medium-term survival in patients with severe alcoholic hepatitis (SAH), particularly in those who are ineligible or unresponsive to corticosteroid therapy. However, given the risk of bias and low certainty of evidence, clinical significance remains uncertain. Confirmation in well-designed studies is needed. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) arises through heterogeneous pathways involving chronic hepatitis B virus infection, hepatitis C virus infection, alcohol-related liver disease, metabolic dysfunction-associated steatotic liver disease, fibrosis, cirrhosis, and environmental exposures. Genome-wide association studies (GWASs) have identified host germline loci associated with HCC susceptibility, but interpretation is complicated by aetiology, ancestry, liver disease stage, and the definition of controls. This narrative review examines current GWAS evidence for HCC, with emphasis on aetiology-specific susceptibility, functional interpretation, cross-disorder genetic effects, and clinical translation. Methods: Studies were identified through iterative searches of PubMed/PMC, publisher pages, academic search tools, and citation tracking, supplemented by targeted searches for major HCC-associated loci. Sources were chosen based on relevance to GWAS discovery, replication, meta-analysis, functional interpretation, polygenic risk modelling, or HCC risk stratification, rather than by a formal systematic review protocol. Results: Viral HCC studies most often implicate immune regulation and antigen presentation, including MICA, HLA-DQ, HLA-DQB1, HLA class I, HCP5, STAT4, DEPDC5, and FAM114A1. Alcohol-related, metabolic, and non-viral HCC studies more often implicate hepatic lipid metabolism, telomere biology, iron metabolism, steatosis, and cirrhosis-related pathways, including PNPLA3, TM6SF2, TERT, HSD17B13, APOE, HFE, and MTARC1. Recent studies increasingly combine GWASs with fine-mapping, functional annotation, transcriptomic analyses, and risk modelling. Conclusions: HCC genetic susceptibility is highly aetiology-specific and overlaps with other liver and metabolic disorders, but discoveries from genetic studies have not yet been translated into routine clinical practice. Future work should prioritise multi-ancestry cohorts, disease-stage-aware controls, functional validation, and prospectively tested genetic risk models. Full article

Objectives: Occupational physical activity (OPA) and leisure-time physical activity (LTPA) have contrasting health effects, a phenomenon known as the “physical activity paradox.” We explored the domain-specific associations between physical activity and non-alcoholic fatty liver disease (NAFLD). Methods: This cross-sectional study included 20,584 Korean workers (10,846 women). Physical activity was assessed using the Global Physical Activity Questionnaire, and NAFLD was assessed using the hepatic steatosis index and the presence of metabolic dysfunction. Logistic regression models were employed to explore the association between each domain of physical activity and NAFLD. The associations are presented as odds ratios (ORs) and 95% confidence intervals (CIs). Results: The prevalence of NAFLD was 30.6% in men and 18.1% in women. For male workers, ≥300 min/week of OPA was positively associated with NAFLD (OR: 1.41; 95% CI: 1.15–1.72), while ≥300 min/week of LTPA was negatively associated with NAFLD (OR: 0.79; 95% CI: 0.67–0.93). In female workers, LTPA was negatively associated with NAFLD from a lower level (OR: 0.63; 95% CI: 0.52–0.78 for 1–149 min/week; OR: 0.71; 95% CI: 0.56–0.89 for 150–299 min/week; OR: 0.58; 95% CI: 0.43–0.78 for ≥300 min/week of LTPA), while OPA had no clear association with NAFLD. Conclusions: OPA and LTPA were differentially associated with NAFLD in workers. Domain- and sex-specific effects of physical activity should be considered for the prevention and management of NAFLD. Full article

Background: MASLD is characterised by chronic inflammation and oxidative stress, which contribute to disease progression. Currently, no effective pharmacological treatment is available, and the first-line treatment remains lifestyle modification, including dietary changes and physical activity. This study aimed to assess the effect of dietary antioxidants, anthocyanins, on the risk of MASLD in a cohort from Southern Italy. Methods: The sample of this study comprised 1, 297 individuals aged between 54 and 64 years from a larger cohort, the NUTRIHEP study cohort. Data on anthocyanin intake were collected using a food-frequency questionnaire. MASLD is diagnosed when fatty liver disease is present in conjunction with at least one cardiometabolic risk factor. Results: Anthocyanin intake was inversely associated with MASLD risk. In Model b, adjusted for adjusted for age, sex, Fasting Glucose, Triglycerides, Diastolic Blood Pressure, Job, Alcohol consumption (g/day), daily energy intake, adherence to the Relative Mediterranean Diet (rMED), Available Carbohydrates, fibre intake, the third quartile (Q3) and the highest intake group (Q4) of anthocyanins showed a negative correlation with MASLD. Analysis of Anthocyanin intake as a continuous variable showed a modest negative association with MASLD risk (OR = 0.990, 95% CI 0.989–0.999), suggesting that higher anthocyanin intake may slightly lower the risk of MASLD. Conclusions: Our study highlights the protective effects of dietary anthocyanins against MASLD. These findings confirm the potential preventive role of dietary polyphenols in MASLD and identify anthocyanins as novel targets for intervention. Full article

Chronic liver disease (CLD) constitutes a major global health burden, with high morbidity and mortality, limited treatment options for several etiologies, and an urgent need for novel therapeutic targets. Fibroblast growth factor 1 (FGF1) is a unique member of the FGF family capable of binding all four FGFR subtypes, thereby regulating multiple signaling pathways including PI3K/AKT, Ras/MAPK, and PLCγ, which are involved in metabolism, cell survival, proliferation, and tissue repair. Emerging evidence highlights the multifaceted and context-dependent roles of FGF1 in CLD. In drug-induced liver injury (DILI) caused by anti-tuberculosis drugs, acetaminophen, or doxorubicin, FGF1 confers protection by restoring bile acid homeostasis, reducing oxidative stress, inflammation, and apoptosis. In Metabolic dysfunction-associated steatotic liver disease (MASLD), FGF1 ameliorates hepatic steatosis, oxidative injury, and insulin resistance through downregulation of SREBP1, upregulation of PPARα, and activation of Nrf2-mediated antioxidant responses. Conversely, in primary sclerosing cholangitis (PSC), FGF1 aggravates ductular reaction, biliary senescence, and liver fibrosis via upregulation of SASP and TGF-β1, suggesting that inhibition of the FGF1/FGFR axis may be therapeutic. For alcohol-related liver disease (ALD), although direct experimental evidence is lacking, FGF1 is hypothesized to confer protection given its known activities against oxidative stress, lipid dysregulation, and cell death. Despite its promise, the mitogenic potential of FGF1 raises safety concerns; however, N-terminally modified FGF1 analogs (e.g., FGF1Δ) retain metabolic benefits with reduced proliferative activity. Collectively, FGF1 represents a versatile and disease-dependent regulator in CLD, warranting further mechanistic studies, safety evaluations, and development of targeted analogs as a novel therapeutic strategy for difficult-to-treat liver diseases. Full article

Background/Objectives: Obesity-associated non-alcoholic fatty liver disease (NAFLD) drives systemic metabolic stress and accelerates chronic kidney disease, yet the mechanistic links remain unclear. Mitochondrial dysfunction has emerged as a central mediator of obesity-induced organ injury. Here, we investigated renal mitochondrial remodeling in a rat model of obesity-associated NAFLD (Ob-NAFLD) and examined the effects of metformin. Methods: Female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for eight weeks, followed by 10 weeks of metformin treatment in designated groups. Kidney tissues were analyzed using biochemical assays, immunoblotting, blue native PAGE, in-gel activity assays, and histological evaluation. Results: In Ob-NAFLD rats, renal ATP levels were elevated despite reduced electron transport chain (ETC) Complex III and increased Complex V expression, reflecting compensatory ATP synthase hyperactivity uncoupled from efficient oxidative phosphorylation. Mitochondrial dynamics were disrupted such that inhibitory phosphorylation of DRP1 was reduced, promoting fission, and total OPA1 expression was decreased with a shift in short-to-long isoform balance, indicating impaired fusion and cristae remodeling. Notably, ATPase inhibitory factor 1 (IF1), a checkpoint that limits ATP synthase overdrive, remained stably expressed, suggesting an adaptive ceiling or failed protective control under chronic metabolic stress. Metformin partially alleviated bioenergetic stress by lowering ATP and modestly restoring Complex III, yet ETC imbalance and structural remodeling persisted, revealing the limitations of metabolic modulation alone. Conclusions: These findings position entrenched mitochondrial dysregulation as a mechanistic bridge linking obesity-driven liver disease to kidney injury. Therapeutic strategies combining metabolic interventions with targeted restoration of ETC coordination, mitochondrial dynamics, and regulatory checkpoints such as IF1 may be required to fully restore renal mitochondrial health and prevent the progression of metabolic kidney disease. Full article

Background/Objectives: Bile acid synthesis disorders (BASDs) represent a distinct category of progressive familiar cholestatic liver disease. A novel targeted mass spectrometry assay was developed for the accurate measurement of the major urinary atypical bile acids and bile alcohols that are biomarkers for HSD3B7, AKR1D1, CYP7B1 and CYP27A1 deficiencies, the four most common BASDs. Methods: Stable-isotope dilution UPLC tandem mass spectrometry was used for the simultaneous quantification of 12 key atypical bile acid biomarkers in urine from patients with BASD. Typical concentration ranges for these metabolites were established from urine samples from patients with biochemically and/or genetically confirmed BASD and compared with non-cholestatic and cholestatic controls. Results: The separation of major 3β-hydroxy-Δ⁵-bile acid sulfates, taurine- and glycine-conjugated 3-oxo-Δ⁴-bile acids, and bile alcohol glucuronides was achieved in a 20 min chromatographic run with intra- and inter-batch imprecisions of <15% for all metabolites. The mean ± SEM urinary concentration of total 3β-sulfated-Δ⁵-cholenoic acids in patients with HSD3B7 deficiency was 704 ± 204 µmol/L (n = 22), approximately 2000-fold higher than in cholestastic patients (n = 168) or non-cholestatic controls (n = 127). Similarly, the concentration of 5β-cholestane-3α,7α,12α,24,25-pentol-glucuronide, the major bile alcohol, in patients with CYP27A1 deficiency was 95 ± 17 µmol/L (n = 12). For CYP7B1 deficiency, two confirmed cases showed elevated levels (average, 7.5 µmol/L) of the glycine conjugate of 3β-sulfooxy-Δ⁵-bile acid. In AKR1D1 deficiency, total 3-oxo-Δ⁴-bile acids in urine were elevated (81 ± 16 µmol/L, n = 48), but concentrations showed overlap with cholestatic and non-cholestatic controls. Conclusions: A novel quantitative tandem mass spectrometry assay is described for the measurement of the major atypical metabolites and biomarkers in urine applicable to the accurate monitoring of treatment responses, and for the first time typical concentration ranges are established for each of these BASDs. Full article

Background: Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH), which causes numerous metabolic changes, leading to non-alcoholic fatty liver disease (NAFLD). Our study explored the suggested role of hypoxia-inducible factor 1-α (HIF-1α) in the pathophysiological mechanisms linking OSA with NAFLD. Methods: This case-control study was conducted at the Sleep Disorders Unit at Qena University Hospital from March 2022 to October 2023, including 64 subjects (48 OSA patients; in a secondary analysis, OSA patients were further stratified according to the presence or absence of NAFLD–16 controls) who were subjected to a polysomnography (PSG) for apnea hypopnea index (AHI) and transient elastography for controlled attenuation parameter (CAP) score and liver stiffness measurement (LSM). Serum levels of HIF 1-α, fasting blood glucose, and fasting insulin were measured. Results: HIF-1α level showed the highest significant value was in the severe group (p = 0.001). Additionally, the severe group had the highest LSM compared to the other groups (p = 0.032). OSA patients with NAFLD, compared to OSA patients without NAFLD, showed significantly higher BMI (42.74 vs. 29.11 kg/m², p < 0.001), homeostatic model assessment for insulin resistance (HOMA-IR) mean score (3.92 vs. 1.21, p < 0.0001), HIF-1α level (6.01 vs. 2.14 ng/L, p = 0.045), and the LSM score (5.55 vs. 3.85 kPa, p < 0.001). HIF-1α showed significant positive correlations with AHI (r = 0.515, p < 0.001), waist circumference WC (r = 0.291, p = 0.045), HSI (r = 0.3, p = 0.038), and CAP score (r = 0.288, p = 0.047). Conclusions: Although serum HIF-1α levels were significantly higher in OSA patients with NAFLD and correlated with indices of hepatic steatosis, HIF-1α was not identified as an independent predictor of NAFLD after adjustment for metabolic confounders, suggesting a potential role of hypoxia-responsive pathways in pathophysiology of NAFLD in OSA. Full article

Hepatocellular carcinoma is challenging to detect at an early stage, and its severity increases over time. Recently, the incidence of hepatocellular carcinoma has increased, partly due to lifestyle-related factors such as excessive alcohol intake, sedentary behavior, and diets high in fat, which contribute to the growing prevalence of fatty liver and hepatitis. Various therapeutic strategies are being explored for hepatocellular carcinoma, among which therapies targeting deubiquitinating enzymes (DUBs) have attracted growing attention. Ubiquitination acts as a crucial modulator in the regulation of intracellular signaling across many diseases. E3 ligase recognizes the target protein and transfers ubiquitin, received from the E2 enzyme, to the lysine residues of the substrate, thereby conferring specificity to the ubiquitination process. Once a ubiquitin chain is attached to a target protein by an E3 ligase, the protein is directed to the ubiquitin–proteasome system (UPS) for degradation. In this process, the 26S proteasome complex recognizes the ubiquitin chain and degrades the target protein, thereby serving as a major mechanism for maintaining protein homeostasis. Through this pathway, cells regulate signal transduction, eliminate abnormal proteins, and perform various essential functions. On the other hand, deubiquitinating enzymes (DUBs) recognize the ubiquitin chains on target proteins and remove them by hydrolyzing the isopeptide bonds of ubiquitin, thereby enabling the target proteins to evade degradation by the proteasome system. Furthermore, deubiquitinating enzymes independently remove ubiquitin from proteins and can serve as central regulators in signaling pathways related to hepatocellular carcinoma. Full article

Non-alcoholic fatty liver disease (NAFLD), now increasingly termed metabolic dysfunction-associated steatotic liver disease (MASLD), is a growing cause of chronic liver disease with limited treatment options. Glucagon-like peptide-1 (GLP-1) receptor agonists, approved for type 2 diabetes and obesity, possess metabolic effects that may render them suitable for treating NAFLD and metabolic dysfunction-associated steatohepatitis (MASH). To evaluate the therapeutic effects of GLP-1 receptor agonists in adults with NAFLD, non-alcoholic steatohepatitis (NASH), MASLD, or MASH. PubMed, Scopus, Embase, and the Cochrane Library were systematically searched using keywords related to NAFLD and GLP-1 receptor agonists. Given heterogeneity in populations, designs, and outcomes, findings were synthesized narratively. The review is registered with PROSPERO (CRD420261337353). Twelve studies met the inclusion criteria. The most consistent outcome was a reduction in hepatic fat, seen with semaglutide, liraglutide, dulaglutide, and beinaglutide. Improvements in liver enzymes, particularly alanine aminotransferase, were less consistent and best regarded as supportive rather than definitive evidence of histological improvement. Histological benefits were strongest for steatohepatitis resolution in non-cirrhotic MASH. Fibrosis findings were mixed, with the greatest benefit in F2–F3 MASH and limited improvement in established cirrhosis. GLP-1 receptor agonists were generally well tolerated, with gastrointestinal symptoms the most common adverse effects. GLP-1 receptor agonists show promising liver-related benefits in NAFLD and MASH, particularly in obesity, type 2 diabetes, or earlier-stage disease. Their effects on advanced fibrosis and long-term outcomes remain uncertain, warranting larger, longer-term studies. Full article

Type 2 diabetes (T2D) is a prevalent disease worldwide that increases the risk of cardiovascular (CV) complications, disability and mortality. While excessive alcohol consumption is harmful, the effects of moderate wine consumption remain debated. This review evaluates whether moderate wine intake affects the risk of developing T2D and its impact on subjects with T2D. Twenty-eight studies were analysed. Evidence suggests an association between moderate wine consumption and the risk of developing T2D, with a J-shaped relationship, and reduced risk observed at low levels. This effect appears more pronounced with red wine, likely related to its higher polyphenol content, and when consumed with meals. On the other side, in patients with T2D, moderate wine consumption has been associated with a reduced risk of CV complications, nephropathy and mortality. It has also been linked to improved lipid profiles and reduced inflammatory markers, without adversely affecting body weight or glycaemic control in well-managed patients. These effects may be enhanced within a Mediterranean dietary pattern, suggesting synergistic actions. However, alcohol intake may increase the risk of hypoglycemia, particularly in patients receiving glucose-lowering therapies. It should be avoided by vulnerable individuals, and those with comorbidities such as MASLD and other significant liver diseases, peripheral neuropathy or other severe conditions. In conclusion, moderate wine consumption may be associated with a reduction in the risk of developing T2D and with several CV benefits in patients with T2D. Vulnerable patients should abstain and individuals who currently do not drink alcohol should not start drinking. If wine is consumed, intake should always remain moderate (as low as possible), within healthy meals and only after individual clinical assessment. Full article