Metabolic dysfunction-associated steatohepatitis (MASH) with significant fibrosis (F2-F3) is a critical stage of metabolic dysfunction-associated steatotic liver disease (MASLD), during which intervention may avert transition to cirrhosis, hepatocellular carcinoma, and liver-related death. The phase 3 ESSENCE trial (NCT04822181) evaluated once-weekly subcutaneous semaglutide 2.4 mg vs. placebo over 240 weeks in adults with biopsy-confirmed MASH and F2-F3 fibrosis. A prespecified interim histologic assessment was performed at week 72 among the first 800 randomized participants. Semaglutide increased MASH resolution without worsening fibrosis and significantly increased the proportion of individuals achieving ≥ 1-stage fibrosis improvement compared with placebo, with a clinically meaningful number needed to treat. These histologic effects coincided with substantial weight reduction (~10%-11% vs. ~2% with placebo) and broad improvements in cardiometabolic risk profiles, including glycemia, blood pressure, lipid levels, and inflammatory biomarkers. Favorable shifts were also observed in non-invasive assessments, including the enhanced liver fibrosis score, vibration-controlled transient elastography, N-terminal type III Collagen Propeptide (PRO-C3), FibroScan-AST (FAST) score, and aminotransferases. Safety outcomes were consistent with the established semaglutide profile in type 2 diabetes and obesity. Here, we critically appraise ESSENCE from clinical and translational perspectives and consider the relative contributions of weight loss vs. potential weight-independent mechanisms. Semaglutide was also situated among emerging latestage therapies, including resmetirom, a thyroid hormone receptor β agonist with demonstrated antifibrotic and antisteatohepatitic activity. Finally, we outline the implications of adopting semaglutide as a disease-modifying agent in MASH with F2-F3 fibrosis, note the study limitations and remaining questions, and argue that combinatorial approaches targeting complementary metabolic and hepatocentric pathways may define the next phase of MASLD management.
Aim: To investigate the effects and potential mechanisms of thrombospondin 1 (Thbs1) in metabolic dysfunction-associated steatohepatitis (MASH).
Methods: Serum Thbs1 concentrations were quantified in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) before and after intervention, and in a biopsy-proven cohort. Moreover, a diet‑induced MASH mouse model was established using a Western diet and fructose water. The involvement of CD47 was evaluated in mice with liver‑specific CD47 overexpression. Further, the immunomodulatory effects of Thbs1 were assessed in lipopolysaccharide-treated RAW264.7 macrophages.
Results: Serum Thbs1 levels significantly decreased in patients with MASLD after treatment. Additionally, patients with MASH exhibited higher Thbs1 levels than non-MASH individuals. This elevated Thbs1 level was modestly associated with histopathological severity. Furthermore, short-term Thbs1 administration was associated with reduced hepatic inflammation and early fibrotic features, accompanied by decreased hepatic macrophage infiltration and M1 macrophage-associated signatures in MASH mice. However, liver-specific CD47 overexpression attenuated the observed effects of Thbs1. In vitro, Thbs1 reduced lipopolysaccharide-induced M1 macrophage-associated signatures and pro-inflammatory cytokine expression.
Conclusion: Thbs1 suppresses M1 macrophage-associated signatures via CD47 signaling, thereby attenuating liver inflammation and early fibrotic features in MASH mice. These data highlight the Thbs1-CD47 axis as a potential stage‑informed target for MASH treatment.
The frequent clinical co-occurrence of intestinal and hepatic disorders points to underlying bidirectional communication along the gut-liver axis. Existing research has primarily focused on metabolic and humoral interactions, including bile acid circulation and portal venous signaling, whereas the autonomic nervous system (ANS) has received comparatively limited attention as an integrative regulatory pathway. This review reframes the axis through a neural perspective, arguing that the ANS functions as a master coordinator of metabolic homeostasis, linking immune regulation, metabolic function, and gut microbiota activity into a unified neuro-immune-endocrine network. The sympathetic and parasympathetic branches, along with the enteric nervous system, modulate barrier integrity, immune cell trafficking, hepatic glucose and lipid metabolism, and microbial composition via neurotransmitter-mediated and receptor-dependent signaling pathways. Dysregulation of this autonomic circuitry disrupts metabolic balance and is implicated in the shared pathophysiology of conditions such as inflammatory bowel disease (IBD) and metabolic dysfunction-associated steatotic liver disease (MASLD). Conversely, neuromodulation strategies, particularly noninvasive vagus nerve stimulation, have demonstrated therapeutic potential in reducing inflammation and restoring metabolic balance. By positioning the ANS as one of the central regulators of gut-liver metabolic cross-talk, this review advances current mechanistic understanding of gut-liver comorbidities and highlights bioelectronic medicine as a promising therapeutic strategy for metabolic disorders. This perspective bridges neuroscience, gastroenterology, and hepatology, offering novel insights for the management of complex, multi-organ metabolic diseases.
Aim: The clinical diagnosis of Wilson disease (WD) remains challenging due to ethnic and phenotypic heterogeneity, as well as the high prevalence of variants of unknown significance (VUS). This study aimed to update the genetic variation spectrum in the Chinese population and reevaluate a subset of VUS to improve the accuracy of genetic diagnosis.
Methods: Patients suspected of having WD and known non-WD controls were selected and underwent ATP7B-targeted sequencing. The variant spectrum was analyzed. Recurrent VUS, particularly those associated with very low ceruloplasmin levels, were further evaluated based on mutational characteristics, including pathogenic variant linkage disequilibrium and zygosity.
Results: We analyzed a total of 679 WD suspects and 251 controls. Of these, 292 patients (282 cases) carried disease-causing variants or VUS. Demographic characteristics were comparable between groups. The most recurrent pathogenic variants - p.Arg778Leu, p.Pro992Leu, and p.Ala874Val - differed significantly from those observed in the Caucasian population. Among the 79 detected VUS, 26 were novel. The most frequent VUS included p.Leu770=, p.Val1297Ile, p.Val1106Ile, p.Ile929Val, p.Ala1003=, p.Ala476Thr, and p.Asp196Glu. Following reevaluation of 9 VUS, we classified p.Val1106Ile, the splice-site variant c.1543+40G>A, p.Ala1018Val, p.Leu1088Ser, p.Gly1335Arg, and the synonymous variants p.Ile1338= and p.Ala1003= as pathogenic candidates. Notably, p.Val1106Ile frequently co-occurred with pathogenic mutations, while p.Leu770= was reclassified as a tag-only variant.
Conclusion: Our study reveals a distinct mutation spectrum in the Chinese population, providing evidence supporting the classification of VUS. The unique mutational patterns observed at specific loci suggest their potential structural significance within the ATP7B protein.
Aim: To examine the genetic and environmental contributions to the association between attention-deficit/hyperactivity disorder (ADHD) symptoms and body mass index (BMI) among children and adolescents, and to assess variation by sex and developmental stage in a non-Western population using a twin design.
Methods: A total of 1,774 same-sex twins aged 6-18 years (1,150 monozygotic and 624 dizygotic) were drawn from the Chinese Child and Adolescent Twin Registry. ADHD symptoms were assessed using the parent-reported Child Behavior Checklist. Univariate and bivariate Cholesky decomposition models were applied to estimate additive genetic, shared environmental, and unique environmental contributions to ADHD symptoms and BMI, as well as their covariance, with analysis stratified by sex and age group (children aged 6-11 years and adolescents aged 12-18 years).
Results: Genetic factors accounted for 46% of the variance in ADHD symptoms and 88% of the variance in BMI. A significant positive phenotypic association was observed between ADHD symptoms and BMI (β = 0.29, P < 0.01), particularly among girls and adolescents. Bivariate twin modeling indicated a modest genetic correlation between ADHD symptoms and BMI in the full sample (rg = 0.13), with higher and statistically significant genetic correlations observed in girls (rg = 0.23) and in children (rg = 0.17). In adolescents, both genetic and unique environmental factors contributed to the association, with relatively greater unique environmental contributions in boys.
Conclusion: These findings indicate etiologically heterogeneous pathways linking ADHD symptoms and BMI across childhood and adolescence by sex and developmental stage, supporting neurobehaviorally informed risk stratification and prevention strategies.
Podocyte lipotoxicity is a fundamental pathogenic mechanism in diabetic kidney disease (DKD), driven by aberrant intracellular lipid accumulation that disrupts cellular integrity and function. This review systematically examines the molecular and metabolic underpinnings of this process, focusing on dysregulated cholesterol efflux, impaired fatty acid oxidation, altered sphingolipid metabolism, and defective lipid droplet homeostasis. These disturbances converge to induce mitochondrial dysfunction, endoplasmic reticulum stress, oxidative damage, and inflammatory activation, collectively leading to podocyte apoptosis and loss. Emerging evidence further illuminates the role of epigenetic regulators, transcriptional networks, and inter-organ signaling in modulating lipotoxic responses. Mechanistic insights into podocyte lipid metabolism provide a critical foundation for developing targeted therapeutic strategies to preserve podocyte function in DKD.
Aim: Diabetic cardiomyopathy is characterized by altered myocardial structure and function, although the underlying mechanism remains unclear. This work evaluated the potential roles of advanced glycation end products (AGEs) and the AGE receptor (RAGE) in diabetes-evoked cardiac defects and the mechanisms involved, with a focus on cuproptosis.
Methods: C57BL/6 mice were induced with diabetes using a high-fat diet and streptozotocin. Diabetic and nondiabetic mice were treated with the RAGE blocker FPS-ZM1, followed by assessment of cardiac geometry, contractile performance, oxidative stress, apoptosis, and cuproptosis.
Results: RNA-seq analysis exhibited differentially expressed cuproptosis-related genes in diabetic hearts, implicating a cuproptosis signature. Levels of AGE and RAGE mRNA were elevated in diabetic hearts. Diabetes triggered cardiac hypertrophy, myocardial tissue fibrosis, impaired fractional shortening, ejection fraction, and cell shortening, alongside mitochondrial ultrastructural and functional defects. Diabetes promoted apoptosis (increased Bax and decreased Bcl2) and cuproptosis [copper transporter 1 (CTR1), ferredoxin 1 (FDX1), dihydrolipoamide S-acetyltransferase (DLAT), and S100 calcium-binding protein A13 (S100A13)], along with dampened Fe-S cluster proteins Aconitase 2 (ACO2) and NADH: ubiquinone oxidoreductase core subunit S8 (NDUFS8). These pathological changes were alleviated by FPS-ZM1, except for CTR1, plasma glucose, and lipid levels. Co-immunoprecipitation and domain mapping favored an interplay between RAGE and the Cu2+-binding protein S100A13. In vitro, methylglyoxal-derived AGE (MG-AGE) and high glucose levels prompted Cu2+ accumulation and/or compromised cardiomyocyte contractile function, reminiscent of in vivo diabetic cardiomyopathy. Inhibition of RAGE, cuproptosis, and S100A13 using FPS-ZM1, tetrathiomolybdate, and amlexanox, respectively, alleviated MG-AGE or high glucose-evoked Cu2+ and cardiomyocyte defects.
Conclusion: These results reveal a role for the RAGE-S100A13-cuproptosis signaling axis in AGE-driven myocardial anomalies in diabetes.
Metabolic dysfunction and Alcohol associated Liver Disease (MetALD) is an emerging phenotype within the steatotic liver disease spectrum, characterized by cardiometabolic risk factors coexisting with alcohol exposure, resulting in synergistic liver injury and fibrosis progression. Therapeutic development remains limited because most steatotic liver disease trials exclude patients with ongoing alcohol use. In contrast, alcohol-associated liver disease (ALD) trials have focused primarily on severe alcohol-associated hepatitis. Current management of patients with MetALD relies on an integrated approach that simultaneously controls alcohol use and cardiometabolic risk. In clinical practice, for patients with MetALD and ongoing alcohol use, therapies aimed at controlling alcohol use remain most critical, given the faster, more progressive disease course related to alcohol as compared to metabolic liver injury. Given the dynamic nature of alcohol intake and metabolic risk factors, longitudinal monitoring of disease stage with noninvasive fibrosis tests is essential. Liver-directed therapies with efficacy in metabolic dysfunction-associated steatotic liver disease (MASLD), including incretin-based agents, fibroblast growth factor 21 analogs, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor beta agonists, may benefit selected MetALD patients. Several agents may modulate both metabolic pathways and alcohol consumption through central reward mechanisms. Specific pharmacotherapies targeting alcohol use (acamprosate, naltrexone) combined with structured psychosocial interventions are effective in controlling alcohol use. Given the lack of dedicated clinical trials in MetALD patients, we synthesized data from clinical trials in MASLD and ALD. We propose adapting these data to inform the design of future clinical trials in patients with MetALD.
Aim: Chronic kidney disease (CKD) is a growing global concern, yet the long-term renal effects of gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP) remain unclear. This study evaluated the associations between GDM or HDP (GDM/HDP) history and CKD risk.
Methods: We used UK Biobank data to perform cross-sectional and prospective analyses. GDM and HDP were identified from self-reports or International Classification of Diseases, Tenth Revision (ICD-10) codes. Multivariable logistic, linear, and Cox regression models were used to assess associations with prevalent CKD and with renal function markers [estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), urate, creatinine], and incident CKD, respectively.
Results: At baseline, 172,133 women were included in the cross-sectional analysis. Prior GDM/HDP was associated with a higher likelihood of prevalent CKD [odds ratio, 1.26; 95% confidence interval (CI): 1.11-1.43] and higher UACR; GDM was also associated with higher eGFR and lower urate and creatinine. In a prospective analysis of 160,635 women over a median follow-up of 14.5 years, GDM/HDP was associated with an increased incident risk of CKD [hazard ratio (HR), 1.33; 95%CI: 1.12-1.59]. GDM alone showed a stronger association with incident CKD (HR: 1.82; 95%CI: 1.39-2.40). In subgroup analyses, the associations of GDM/HDP, GDM, and HDP with incident CKD remained largely consistent across strata of age, body mass index (BMI), baseline eGFR, and major chronic conditions.
Conclusion: Prior GDM/HDP was associated with subsequent subclinical and clinical renal impairment, supporting the inclusion of reproductive history in CKD risk assessment and the need for targeted prevention and long-term monitoring.