Liver Disease Research Articles

Statins, traditionally viewed with caution in liver disease due to concerns about hepatotoxicity, are now increasingly recognized as both safe and potentially beneficial in this population. Recent evidence demonstrates that clinically significant liver injury from statins is exceedingly rare, while mild aminotransferase elevations are usually transient and adaptive. Large trials and real-world studies confirm that patients with chronic liver disease, including nonalcoholic fatty liver disease, viral hepatitis, and compensated cirrhosis, tolerate statins well. Importantly, statins offer more than lipid-lowering: pleiotropic effects such as improved endothelial function, antifibrotic activity, and reductions in portal hypertension may alter the natural history of liver disease. In nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, statins not only provide substantial cardiovascular risk reduction but also improve aminotransferases and may slow fibrosis progression. In chronic viral hepatitis B and C, statin exposure is associated with slower fibrosis progression, fewer decompensations, and significant reductions in hepatocellular carcinoma risk, with dose-response relationships supporting causality. In alcoholic liver disease and cirrhosis, statins have been linked to lower mortality and decompensation, mediated in part by reductions in portal pressure, though caution is warranted in advanced decompensated states. Postliver transplant, statins are commonly indicated for dyslipidaemia and are associated with improved patient and graft survival when managed alongside immunosuppressant interactions. Overall, statins should be considered safe allies in patients with chronic liver disease, offering cardiovascular protection and potential hepatic benefits, shifting the paradigm from foe to friend.

Fibrosis is a key pathological feature of autoimmune liver diseases (AILD). This study evaluates the diagnostic potential of apparent diffusion coefficient (ADC) values from diffusion-weighted imaging (DWI) for liver fibrosis staging, liver damage, and inflammation in AILD patients. This retrospective study analyzed the diagnostic performance of ADC values from DWI in 157 AILD patients. Liver biopsy served as the gold standard for fibrosis staging. The relationship between ADC values and liver function markers (AST, ALT) and inflammatory cytokines (IL-17, TNF-α) was assessed. To evaluate diagnostic accuracy, ADC values were compared across different fibrosis stages (S0 to S4) and inflammation grades (G0 to G4). ADC values decreased progressively with increasing fibrosis stages and inflammation grades. Notably, ADC values were significantly lower in S4 compared to S0, with an AUC of 0.91. Pearson correlation analysis revealed significant negative correlations between ADC and serum IL-17 (r = -0.39, p < 0.001), TNF-α (r = -0.43, p < 0.001), as well as liver function markers, ALT (r = -0.49, p < 0.001) and AST (r = -0.46, p < 0.001). ROC analysis showed optimal ADC cut-off values for distinguishing fibrosis stages: 1.47 × 10-³ mm²/s for ≥ S1 (AUC = 0.90), 1.35 × 10-³ mm²/s for ≥ S2 (AUC = 0.88), 1.24 × 10-³ mm²/s for ≥ S3 (AUC = 0.90), and 1.12 × 10-³ mm²/s for S4 (AUC = 0.91). This study highlights ADC values from DWI as a reliable non-invasive biomarker for assessing liver fibrosis and inflammation in AILD patients.

Endoscopic sleeve gastroplasty (ESG) has gained recognition as a minimally invasive endoscopic treatment for obesity; however, clinical data in Japan is lacking. A retrospective review was conducted of 91 individuals with obesity who underwent ESG between January 2023 and November 2024. Eligibility included BMI ≥ 27.5 with at least one obesity-related comorbidity and preference for non-surgical therapy. Primary outcomes were the percentage of total weight loss (%TWL) at 1 month, 6 months and 1 year, and the rate of complications. The mean %TWL was 10.1% at 1 month, 15.2% at 6 months and 19.8% at 1 year. The follow-up completion rates were 100% at 1 month, 96.7% at 6 months and 87.9% at 12 months. Improvement in obesity-related comorbidities was observed in 57.1% of individuals with hypertension, 94.7% with dyslipidemia, 91.7% with diabetes, 96.9% with fatty liver disease and 75.0% with obstructive sleep apnea. One adverse event (1.1%) occurred, a pyriform sinus injury that resolved with conservative management; no severe complications were observed. ESG demonstrated favourable short-term weight loss and safety outcomes in Japan. These findings suggest ESG as a viable treatment option for Japanese individuals with obesity.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of cirrhosis. Vibration Controlled Transient Elastography (VCTE) measurements are often captured in text-based reports and not readily accessible for clinical research. Large language models (LLMs) show promise for curating information from unstructured documentation, but their efficiency for MASH and VCTE extraction are unclear. We used a cohort of 493 patients with compensated MASH cirrhosis. We compared the abilities of GPT-4o and Claude 3.5 Sonnet for identifying the presence of MASH and extracting maximum VCTE stiffness and Controlled Attenuation Parameter (CAP) measurements from clinical documentation. We ran a cost analysis of the LLMs. As exploratory analysis, we used LASSO-Cox to associate LLM-extracted features with death or decompensation. For identifying MASH in clinical notes, GPT-4o and Claude 3.5 achieved F1-scores of 90.5% and 80.0%. For identifying peak VCTE measurements, GPT-4o achieved 99.3% and 99.1% accuracies for stiffness and CAP, while Claude 3.5 achieved 93.3% and 94.1% accuracies. LLM extraction of one variable required ~ 2000 tokens per note, with a cost of ~ $0.012/note for GPT-4o and ~ $0.014/note for Claude 3.5. In LASSO-Cox regressions, VCTE stiffness (HR 1.03, 95% CI 1.01-1.05, p = 0.016) and CAP score (HR 0.99, 95% CI 0.99-1.00, p = 0.029) were statistically significant predictive variables for death or decompensation. LLMs can extract MASH presence and VCTE parameters from documentation with high accuracy and low cost. When incorporated into survival analyses, LLM-extracted variables are associated with important clinical outcomes. Given the growing availability of LLMs, liver diseases researchers should incorporate these methods to facilitate real-world studies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form metabolic dysfunction-associated steatohepatitis (MASH) are prevalent chronic liver diseases that are closely linked to metabolic syndrome, type 2 diabetes, and cardiovascular complications. Despite their rising incidence and growing socioeconomic burden, effective therapies remain limited. Traditional preclinical models often fail to replicate the complexity of human MASLD, particularly in capturing the interplay between patient-specific predisposition, metabolic dysfunction, immune activation and progressive fibrosis. In this review, a comprehensive overview of emerging human-based in vitro and ex vivo platforms is provided for use in MASLD research, including conventional 2D cultures, organoids, 3D spheroids, precision-cut liver slices, microphysiological systems, and bioprinted constructs. Their utility is evaluated for modeling different stages of MASLD and MASH and their alignment with key disease hallmarks is discussed. Furthermore, the different models are assessed for their capability to model pathophysiologically relevant nutritional exposure, to emulate genetic risk factors, to reflect the complex hepatic cell repertoire and to conduct high-throughput drug screenings. Recent successful applications of MASLD and MASH models are highlighted in drug discovery and development. Together, these insights aim to guide the refinement of human MASLD models to narrow the translational gap in MASH drug development.

Background: Patients with advanced non-malignant diseases experience pain, dyspnoea and fatigue, requiring a rehabilitation approach within palliative care. Aim: To identify components of non-pharmacological interventions for symptom self-management for patients with non-malignant chronic disease. Method: This scoping review identifies: (1) systematic reviews of symptom self-management interventions for breathlessness, pain and fatigue in chronic lung, heart, renal and liver disease; (2) primary studies in low- and middle-income countries to identify intervention components, contextual factors, facilitators and barriers to symptom self-management. Six databases were searched, records exported to Rayyan and deduplicated. Following screening for inclusion, extraction was conducted. We conducted a narrative synthesis of intervention components and implementation factors, and content analysis of barriers and facilitators to interventions. Results: Thirty-one articles were included (21 systematic reviews and 10 primary studies). The populations studied had chronic lung disease (n = 19), heart disease (n = 12), chronic renal disease on dialysis (n = 2) and none had hepatic disease. The three most common intervention components were information, training and rehearsal for practical self-management activities and lifestyle support. Common patient barriers included motivation, adherence and health literacy, while facilitators encompassed knowledge, support and family involvement. The availability of healthcare workers can impact implementation, but remote access options should be considered. Conclusion: Disease and management information for patients and their family members, along with support for home application, form the foundation for effective symptom self-management. Contribution: Symptom self-management for non-malignant chronic diseases is uncommon in low-resource settings. This review outlines the necessary components and implementation considerations.

This practice recommendation serves as an update to the 2023 AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease (NAFLD), now known as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) (3) and provides implementable guidance on patient selection for treatment, consideration of comorbidities, and monitoring of treatment safety and efficacy of semaglutide. FDA-indication and Practice Recommendation: The Wegovy® formulation, whose main ingredient is semaglutide, received accelerated FDA approval in August 2025 for treating MASH with moderate to advanced fibrosis (consistent with stages F2-F3 fibrosis), based on interim results of the phase 3 ESSENCE trial where 72 weeks of 2.4mg/week subcutaneous injection resulted in achievement of both primary histologic endpoints: 1) resolution of MASH without worsening of fibrosis (62.9% vs 34.3% placebo, p <0.001 ) and 2) ≥1 stage reduction in liver fibrosis without worsening of MASH (36.8% vs 22.4% placebo, p <0.001); final approval awaits long-term outcomes. Patient Selection: Candidates should have MASH with stage 2-3 fibrosis, identified using noninvasive tests (NITs) such as VCTE (8-15kPa), MRE (3.1-4.4kPa), or ELF (9.2-10.5), rather than liver biopsy, which is impractical and unnecessary for most patients. In those with VCTE (15-20kPa), MRE (4.4-5kPa), or ELF (10.5-11.3), an individualized decision to treat should be based on exclusion of cirrhosis with another confirmatory NIT, or cross-sectional imaging excluding nodular-appearing liver contour and signs of portal hypertension, or a platelet count of <150,000/mm 3 . While semaglutide is not approved to treat patients with MASH cirrhosis (VCTE>20kPa, MRE>5.0kPa, ELF>11.3 and/or evidence of portal hypertension), those with compensated cirrhosis who are receiving semaglutide for another FDA-approved indication should be monitored carefully. Monitoring and Safety: Semaglutide showed a favorable hepatic safety profile in the ESSENCE trial, with no discontinuations due to liver enzyme elevations. Routine hepatic panels are recommended only as clinically indicated. The most common adverse events were gastrointestinal (nausea, diarrhea, constipation, vomiting), generally mild and transient; patient education and dose titration help improve tolerance. Clinicians should monitor for rare but serious risks, including acute kidney injury (from dehydration), symptomatic gallbladder disease, pancreatitis, thyroid C-cell tumors, retinopathy progression, and lean mass loss. Treatment Response and Concomitant Therapy: Lifestyle modification remains the cornerstone of MASLD/MASH management alongside semaglutide. Combination use with resmetirom at the dose of 2.4mg/week has not been studied. While no NITs reliably predict histologic response at the individual patient level, reductions from baseline to 72 weeks of treatment suggest significant improvement in MASH resolution (ALT >17U/L or ≥20%; CAP ≥30%) and fibrosis improvement (VCTE LSM ≥30%; MRE LSM ≥20%; ELF≥0.5). Non-response may be suspected if ALT or NITs worsen. Benefit is uncertain if sub-optimal response and may require an individualized approach and further follow-up.

Synergistic effects of outdoor nighttime light, air pollution, and PM2.5 components on multimorbidity risk of hypertension, dyslipidemia, and liver diseases: a prospective cohort study.

To analyze the diagnostic performance of tissue attenuation imaging (TAI), tissue scatter-distribution imaging (TSI) and ultrasound-based fat fraction (USFF) in suspected metabolic-associated fatty liver disease (MASLD), using histopathological hepatic steatosis as the reference standard. This was a retrospective analysis of prospectively recruited participants with suspected MASLD from August 2022 to November 2023. TAI, TSI and USFF were measured. Spearman correlation analysis was used to evaluate the correlation of TAI, TSI and USFF with hepatic steatosis. The diagnostic performance for detecting hepatic steatosis was evaluated by multiclass or binary receiver operating characteristic (ROC) curves. A total of 264 participants were enrolled, including 227 with biopsy-confirmed MASLD and 37 with normal liver biopsy results. Compared with TAI and TSI, USFF had a better positive correlation with hepatic steatosis in the overall set (rUSFF = 0.62, rTAI = 0.57, rTSI = 0.56; all p < 0.001). Multiclass ROC analysis indicated TAI, TSI and USFF exhibited only modest to suboptimal diagnostic performance for all hepatic steatosis (S0-S3) in index (volume under surface (VUS) 0.21-0.51) and validation set (VUS 0.18-0.34). However, binary ROC curves revealed TAI, TSI and USFF yielded the highest AUCs in detecting mild or greater hepatic steatosis in index (AUC 0.95-0.98) and validation set (AUC 0.92-0.96). USFF has a good correlation with histopathological hepatic steatosis grade. TAI, TSI and USFF might be potential quantitative diagnostic tools for detecting mild hepatic steatosis in MASLD, though further validation in larger and more balanced cohorts is needed. Question How is the diagnostic performance of quantitative ultrasound parameters in suspected metabolic dysfunction-associated steatotic liver disease using liver biopsy as the reference standard? Findings Tissue attenuation imaging, tissue scatter-distribution imaging and ultrasound-based fat fraction show promising diagnostic potential for mild hepatic steatosis in metabolic dysfunction-associated steatotic liver disease. Clinical relevance Tissue attenuation imaging, tissue scatter-distribution imaging, and ultrasound-based fat fraction might be potential noninvasive tools for detecting mild hepatic steatosis and conducting large-scale follow-ups in metabolic dysfunction-associated steatotic liver disease.

The majority of hepatocellular carcinoma (HCC) cases arise in patients with cirrhosis, with known major risk factors of hepatitis B (HBV) or C (HCV) infection, metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol-associated liver disease (ALD). However, the impact of additional risk factors that act independently or jointly on the pathogenesis of HCC in cirrhosis patients is unknown. The aim of this study was to determine whether sleep, sedentariness, or physical activity levels play a role in the progression of cirrhosis to HCC. We systematically collected data on sleep, sedentary time, and physical activity from the ongoing prospective study, the Texas HCC Consortium Cohort, which recruited patients with cirrhosis from December 2016 and followed up until HCC development, death, or May 2024. Hazard ratios (HRs) were calculated using Fine-Gray competing risk regression models to evaluate the independent association between sleep, sedentary, and physical activity levels with the risk of HCC overall and in groups stratified by major HCC risk factors. Of 3940 patients with cirrhosis (mean age = 59.9years, 39.1% women), 9.3% of patients had active HCV, 34.6% had MASLD, 41.5% had MetALD, and 3.2% had ALD only. In total, 208 patients developed incident HCC (annual incidence rate, 2.37% [95% CI 2.07, 2.72%]). After adjustment for demographic and clinical factors, absent levels of light physical activity (HR = 0.92 [0.57-1.47]), excessive sitting time (HR = 0.91 [0.57-1.44]), and reduced sleep duration (HR = 0.92 [0.65-1.29]) were not associated with an increased risk of HCC development. There were no associations with increased risk of HCC development across all sub-groups examined. In this study, the risk of HCC in patients with cirrhosis was not significantly affected by level of light physical activity, sedentariness, or sleep across all major etiologies of cirrhosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease, often linked to telomere-related gene (TRG) mutations in familial forms. Telomere biology disorders can also manifest with systemic features such as bone marrow failure and liver disease. We report a 72-year-old woman with a family history of pulmonary fibrosis and premature hair greying. The patient had a history of bronchopneumonia at age 20 and pulmonary tuberculosis at age 23. Genetic testing identified a novel heterozygous nonsense variant in Regulator of Telomere Elongation Helicase 1 (RTEL1) (NM_001283009.2:c.2962C > T; p.Gln988Ter). This variant introduces a premature stop codon, likely leading to loss of function. The variant, absent from major population databases, was classified as "likely pathogenic" according to ACMG criteria. RTEL1 encodes a DNA helicase essential for DNA replication and telomere maintenance, and its disruption contributes to epithelial cell dysfunction in pulmonary fibrosis. This case expands the mutational and clinical spectrum of RTEL1-associated interstitial lung diseases and underscores the importance of genetic testing in patients with familial pulmonary fibrosis.

Nonalcoholic fatty liver disease (NAFLD) is a common hepatic disorder linked to metabolic syndrome. Endothelial dysfunction is crucial in NAFLD progression. Endocan, a marker of endothelial injury, has been studied in NAFLD, and we aim to systematically evaluate these findings. PubMed, Scopus, Embase, and Web of Science were searched for studies measuring endocan levels in NAFLD patients compared to healthy controls. A random-effects meta-analysis was performed to estimate the standardized mean difference (SMD) with a 95% confidence interval (CI). Ten studies with 1045 participants (mean age 44.1 ± 9.8 years, 48.8% male) met inclusion criteria. Meta-analysis showed no significant difference in endocan levels between NAFLD patients and controls (SMD 0.03, 95% CI -0.59 to 0.65, p = 0.931). The diagnostic accuracy of endocan for NAFLD varied (AUC 0.647-0.867). Endocan was linked to endothelial dysfunction, atherosclerosis, and coronary artery disease in NAFLD patients. Although serum endocan levels did not differ between NAFLD and controls, its role in endothelial dysfunction and disease prognosis suggests potential clinical relevance. Larger studies are needed to confirm these findings.

Liver cirrhosis is a progressive chronic disease with high morbidity and mortality, thereby posing a major challenge to global health. Evidence suggests that thyroid dysfunction, particularly hypothyroidism, is linked to liver diseases. Hypothyroidism disrupts metabolism, immune homeostasis, and inflammatory pathways, processes central to cirrhosis pathophysiology. However, its causal role and molecular mechanisms remain unclear. The study initiated by analyzing the association between thyroid dysfunction and cirrhosis through retrospective analysis of longitudinal data obtained from the Medical Information Mart for Intensive Care clinical database. To assess genetic correlation, we applied linkage disequilibrium score regression, followed by bidirectional Mendelian randomization to explore potential causal relationships. Through transcriptome-wide association studies, we identified candidate genes, which were then prioritized using a combination of weighted gene co-expression network analysis and differential gene expression data integration. To interpret the biological relevance of these genes, we conducted functional enrichment analyses. We further explored gene function at the cellular level by leveraging single-cell RNA sequencing (scRNA) to map cell-specific expression patterns, analyze intercellular communication, and simulate gene knockouts. Finally, we performed molecular docking and phenome-wide Mendelian randomization to identify potential therapeutic compounds targeting the prioritized genes. Through a combination of observational and genetic insights, we established a causal relationship between hypothyroidism and cirrhosis, identifying hypothyroidism as a risk factor for cirrhosis. Subsequent multi-omics analyses highlighted HLA-DQA1 and CD27 as potential therapeutic targets. ScRNA revealed key roles of these molecules in macrophages and CD8 ⁺ T cells, and simulated knockouts confirmed their importance in T cell activation and lymphocyte proliferation. Finally, molecular docking analysis identified glycyrrhizic acid and levothyroxine sodium as candidate drugs targeting HLA-DQA1 and CD27, while phenome-wide Mendelian randomization analysis revealed potential adverse effects associated with these targets. This study is the first to reveal a causal relationship between hypothyroidism and cirrhosis, potentially driven by immune dysregulation mediated by HLA-DQA1 and CD27. These findings offer novel insights into disease progression and identify HLA-DQA1 and CD27 as potential therapeutic targets, with glycyrrhizic acid and levothyroxine sodium as promising candidate drugs.

Emerging evidence suggests that adipose tissue is not just a fat depot but a metabolically active organ that plays a central role in connecting obesity with its comorbidities. Understanding the complex interactions between adipocytes and neighboring cell types in obesity requires models that accurately replicate adipocyte behavior within their natural environment. Three-dimensional (3D) adipocyte cultures mimic the native tissue microenvironment by incorporating the spatial architecture as well as cell-cell and cell-extracellular matrix (ECM) interactions present in vivo, offering improved platforms for (patho)physiological adipose tissue modeling. 3D models of adipose tissue dysfunction enable the study of complex cellular crosstalk, such as adipocyte cancer cell interactions in breast, colorectal, bone, and pancreatic cancers; epicardial and pericardial adipocyte-myocardial cell dynamics in obesity-related cardiac dysfunction; and adipocyte-hepatocyte interactions in the development of non-alcoholic fatty liver disease, among other critical pathophysiological processes. In this review, we first discuss 3D models of adipose tissue and current strategies for mimicking the obesogenic microenvironment, including dietary stimulation of hyperlipidemia and hyperglycemia, as well as the incorporation of oxygen gradients, proinflammatory cytokines, and immune cells. Secondly, we examine 3D co-culture platforms that incorporate disease-associated/dysfunctional adipocytes with various cell types, such as cancer cells, cardiac cells, hepatocytes, immune cells, endothelial cells, and fibroblasts, to model intercellular and interorgan crosstalk in obesity. Lastly, we provide insights into enhancing the physiological relevance of dysfunctional adipose tissue models and their co-culture systems while discussing future directions in tissue engineering aimed at improving clinical translation and reducing obesity related complications and mortality.

In the absence of long-term research with respect to the impact of a ketogenic diet (KD) on liver disease progression, further investigation into the screening for liver enzymes is useful in attempting to elucidate whether a KD may result in positive or negative effects. The goal of this study was to thoroughly examine how a KD affects liver health. The PubMed/Medline, Web of Science, Scopus, Cochrane Library, and Embase databases were searched to find pertinent randomized controlled trials (RCTs). This systematic review featured 20 RCTs investigating the impact of a KD on liver enzymes and liver stiffness. A random-effects model analysis was undertaken, yielding pooled weighted mean differences and 95% CIs. A quantitative meta-analysis showed that a KD has a significant lowering effect on levels of aspartate aminotransferase (AST) [weighted mean difference (WMD): -3.56 U/L; 95% CI: -6.61, -0.51], alanine aminotransferase (ALT) (WMD: -3.03 U/L; 95% CI: -5.26, -0.81), gamma-glutamyl transferase (GGT) (WMD: -12.25 U/L; 95% CI: -22.08, -2.42), and alkaline phosphatase (ALP) (WMD: -5.29 U/L; 95% CI: -9.85 to -0.74). However, the findings obtained from the meta-analysis showed that a KD has no significant effect on liver fibrosis (liver stiffness) (WMD: 0.40; 95% CI: -0.23, 1.04). The findings also showed that a KD followed for a duration of less than 12 weeks caused greater reductions in liver enzymes, including AST, ALT, and GGT, in people with a BMI of less than 30. In general, KDs can reduce traditional liver enzyme levels (ALT, AST, ALP, and GGT), but they appear to have no significant effect on liver stiffness.

Appropriate dietary measures can be pivotal in ensuring optimal outcomes for individuals with non-alcoholic fatty liver disease (NAFLD). However, limited data are available regarding the knowledge, attitude, and practice (KAP) of dietary management of NAFLD. This study assessed the KAP of dietary management of NAFLD in patients diagnosed with NAFLD. This cross-sectional study was conducted in Southwest China between July and November 2023. Participants diagnosed with NAFLD were enrolled using convenience sampling. The self-designed questionnaire demonstrated good internal consistency (Cronbach's α = 0.896) and covered demographic characteristics and KAP of dietary management of NAFLD. A total of 357 valid questionnaires were analyzed. The mean knowledge score was 19.75 ± 10.45 (possible range: 0-35), the mean attitude score was 51.21 ± 6.86 (possible range: 12-60), and the mean practice score was 6.58 ± 1.66 (possible range: 0-16, 41.13%), indicating poor knowledge, positive attitudes, and poor practice. The knowledge scores weakly correlated with attitude (r = 0.488, P < 0.001) and practice (r=-0.207, P < 0.001) scores. The attitude scores were weakly correlated with the practice scores (r=-0.305, P < 0.001). The path analysis revealed that knowledge positively influenced attitude (β = 0.33, P < 0.001), while attitude negatively influenced practice (β=-0.06, P < 0.001). However, knowledge does not directly influence practice. Patients with NAFLD in Sichuan exhibited poor knowledge, positive attitudes, and poor practice toward dietary management of NAFLD. Educational interventions should be designed to enhance their KAP of dietary management in NAFLD.

Prevalence and health checkup-based detection of metabolic dysfunction-associated steatotic liver disease in Japanese young adults.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally increasing metabolic disorder associated with serious health complications. The molecular mechanisms linking stress-response proteins to hepatic lipogenesis in MASLD remain poorly understood. Here, we identified GADD45β as a key suppressor of de novo lipogenesis through SIRT1 stabilization. In both methionine-choline-deficient (MCD) diet-fed mice and palmitic acid (PA)-treated hepatocytes, GADD45β deficiency exacerbated lipid accumulation and upregulated lipogenic genes (SREBP1, FASN, ACC). Mechanistically, GADD45β directly bound to SIRT1 and inhibited its ubiquitination, thereby prolonging SIRT1 protein stability. Enhanced SIRT1 stability increased AMPK phosphorylation, which suppressed SREBP1-mediated transcription of lipogenic targets. Crucially, hepatic overexpression of GADD45β reversed PA-induced steatosis in vitro. Our study uncovered a GADD45β/SIRT1-/AMPK axis as a central regulator of hepatic lipogenesis, proposing GADD45β as a therapeutic target for MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious disease and increasingly prevalent in children. MASLD is associated with health consequences such as type 2 diabetes, and cardiovascular disease. While, vitamin E is a potent antioxidant that has been proposed to improve liver function and cardiometabolic health including liver markers, lipid profile, glycemic control, and anthropometric measurements. A comprehensive search was conducted up to March 2025. Data on anthropometric measures, liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT)), glycemic indices (fasting blood sugar (FBS), insulin, homeostatic model assessment for insulin resistance (HOMA-IR)), lipid profiles (total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)), and serum vitamin E levels were extracted. Statistical analyses were performed using a random-effects model. Eleven RCTs involving 665 participants were included in this study. Vitamin E significantly reduced ALT (weighted mean difference (WMD)= -5.23 U/L;95% confidence interval (CI): -7.72, -2.75; P< 0.001) and AST (WMD= -3.00 U/L;95% CI: -4.59, -1.41; P< 0.001), reflecting improved liver function. It also decreased TC (WMD= -5.77 mg/dL;95% CI: -11.46, -0.09; P= 0.04) and HOMA-IR (WMD= -0.82;95% CI: -1.28, -0.37; P< 0.001), while significantly increasing serum vitamin E levels (WMD= 9.16 mg/L;95%CI: 3.29, 15.03; P=0.002). No significant changes were observed in the BMI, GGT, FBS, insulin, LDL, HDL, or TG levels. Vitamin E supplementation in pediatric MASLD appears to favorably influence key liver enzymes such as ALT, AST and certain metabolic factors including TC, and HOMA-IR levels, supporting its potential role as adjunctive therapy.

Coronary CT angiography (CCTA) derived pericoronary fat attenuation index (FAI) is a reliable quantitative biomarker of vessel inflammation. However, whether this novel index mediated the relationship between metabolic dysfunction-associated fatty liver disease (MAFLD) and major adverse cardiovascular events (MACEs) remains unknown. From January 2019 to December 2022, consecutive patients with stable chest pain who underwent CCTA and unenhanced abdominal CT were prospectively enrolled. All participants were divided into two groups-with MAFLD and without MAFLD according to abdominal CT results. The primary end point was MACEs, defined as cardiac death, nonfatal myocardial infarction, and late revascularization. A total of 135 participants with MAFLD and 232 without MAFLD were included in our study. The multivariate logistic regression analysis revealed that MAFLD was significantly associated with obstructive coronary artery disease (OR = 1.86, p = 0.024), high-risk plaque features ≥ 2 (adjusted OR = 2.34, p < 0.001), CT derived fraction flow reserve ≤ 0.8 (adjusted OR = 1.88, p = 0.006), FAI ≥ -70.1HU (adjusted OR = 3.25, p < 0.001) after adjusted for traditional risk factors. Participants with MAFLD showed a lower 36-month MACE-free survival rate than participants without MAFLD (54.0% vs. 83.5%, log-rank p < 0.001). In addition, MAFLD was significantly associated with MACEs (HR = 3.65, 95%CI: 1.83, 7.26, p < 0.001). Furthermore, mediation analysis revealed that FAI mediated 46.8% for the relationship between MAFLD and MACEs. MAFLD is associated with CCTA derived plaque characteristics, including geometric, physiologic and inflammatory status. The relationship between MAFLD and MACEs might be partially mediated via coronary inflammation, which could be captured by FAI. Not applicable.