Aim: To investigate the role of yohimbine (YH) in diabetic nephropathy (DN) progression and identify its underlying molecular mechanisms.

Methods: Human renal proximal tubular epithelial cells (HK-2) were cultured with high glucose (HG) and treated with varying doses of YH. Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. Inflammatory markers and oxidative stress were measured. Male diabetic C57BLKS/J-LepR (db/db) mice received YH (2.5, 5, or 10 mg/kg) daily for eight weeks. Circular RNA (circRNA) microarray analysis was performed on HG-induced HK-2 cells. RNA pull-down assays combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to identify circGNB1-interacting proteins. Cellular localization and protein expression were determined through fractionation, RNA fluorescence in situ hybridization (RNA-FISH), and western blotting.

Results: YH significantly enhanced viability of HG-induced HK-2 cells while reducing inflammatory factors and oxidative stress markers. These protective effects were confirmed in db/db mice, where YH reduced blood glucose, urinary albumin-to-creatinine ratio, and blood urea nitrogen levels. CircRNA microarray identified circGNB1 as the most significantly upregulated gene in YH-treated HG-induced cells. RNA pull-down assays identified cell division autoantigen 1 (CDA1) as a circGNB1-interacting protein. CircGNB1 positively regulated CDA1 expression at the protein level in HK-2 cells. CDA1 knockdown significantly decreased cell viability and counteracted the protective effects of YH treatment.

Conclusion: Our study identifies a novel YH/circGNB1/CDA1 axis in DN progression. YH attenuates oxidative stress through upregulation of circGNB1, which interacts with and regulates CDA1 protein expression, thereby mitigating HG-induced renal cell damage. These findings provide new insights for developing therapeutic strategies for DN.

Aim: Drug-induced fatty liver disease (DIFLD) is an increasing concern due to both new and existing medications. This study aims to analyze trends in drug associations with DIFLD, identify vulnerable populations, and provide insights for better prevention and management strategies.

Methods: Reports of steatotic liver disease (SLD) and liver failure from the Food and Drug Administration’s Adverse Event Reporting System (FAERS) for the period 2004-2023 were analyzed separately after deduplication per guidelines. Drugs were categorized by therapeutic class, and trends were assessed using linear regression. Subgroup analyses addressed age, sex and regional difference.

Results: Between 2004 and 2023, a total of 15,269 SLD cases were reported in FAERS, with annual cases increasing significantly from 481 in 2004 to 1,413 in 2023 (+46.00 cases/year). Among implicated drug classes, monoclonal antibodies (MAbs), antipsychotics, and disease-modifying antirheumatic drugs were the most frequently reported, with MAbs showing the most rapid increase in reporting rate (+11.77 cases/year). Adalimumab was the leading single drug linked to DIFLD, accounting for 5.81% of all reported cases. Subgroup analyses revealed that adults aged 18-64 years (75.65%) and females (59.12%) were the most affected populations. Notably, hypoglycemic agents showed a pronounced increase in female cases. The United States accounted for 45.44% of cases, with distinct drug-class patterns observed across regions.

Conclusion: This study reveals significant trends in the association between drugs and DIFLD and liver failure, stressing the need for region-specific pharmacovigilance and tailored interventions to mitigate risks and optimize treatment outcomes.

Despite substantial advances extending human lifespan, the gap between healthspan and lifespan continues to widen, with neurodegenerative diseases (NDDs) and metabolic disorders representing major contributors to this disparity. Growing epidemiological and genetic evidence indicates a bidirectional relationship between NDDs and metabolic disorders, suggesting shared pathophysiological mechanisms that transcend organ-specific boundaries. In this narrative review, we sought to explore the interconnections between neurodegeneration and metabolic dysfunction through the lens of the twelve established hallmarks of aging. We conducted a comprehensive literature search across multiple databases (PubMed, Google Scholar, Scopus, ScienceDirect) from January 2013 to April 2025, focusing on studies examining aging hallmarks in both NDDs (particularly Alzheimer’s disease and Parkinson’s disease) and metabolic disorders (obesity, type 2 diabetes mellitus, and metabolic dysfunction-associated steatotic liver disease). Our analysis reveals that all twelve hallmarks - i.e., genome instability, telomere attrition, epigenetic alterations, loss of proteostasis, impaired autophagy, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis - may serve as convergence points linking these seemingly disparate conditions. These findings support an integrated pathophysiological model wherein aging-related processes simultaneously promote neurodegeneration and metabolic dysfunction through shared molecular pathways. Understanding these mechanistic intersections offers promising opportunities for developing therapeutic interventions that could simultaneously target both neurodegenerative and metabolic diseases, potentially helping to close the healthspan-lifespan gap.

This narrative review examines current trial design strategies and highlights the limitations of traditional models in capturing the heterogeneity and dynamic nature of metabolic dysfunction and alcohol-associated liver disease (MetALD). MetALD represents an increasingly prevalent and clinically distinct phenotype that reflects the convergence of metabolic risk factors and alcohol-related liver injury. Designing effective clinical and translational research in MetALD presents unique challenges as its burden continues to rise. Novel frameworks, such as adaptive and enrichment designs, offer improved pathways for patient stratification and intervention testing. The integration of molecular and translational biomarkers to inform diagnosis, prognosis, and therapeutic responsiveness is central to this evolution. This review also addresses critical methodological issues, including the need for harmonized definitions, careful endpoint selection, and real-world applicability of findings. Emerging therapies targeting steatosis, inflammation, fibrosis, gut-liver axis dysfunction, and metabolic pathways are now entering clinical development and require trial designs tailored to the multifaceted biology of MetALD. In this context, the article also discusses the importance of early-phase proof-of-concept studies and innovative approaches for combination therapies. Ethical and operational considerations, such as alcohol use thresholds, stigma, and disparities in access to care, further influence trial feasibility and generalizability. Finally, multidisciplinary collaboration across hepatology, addiction medicine, endocrinology, and trial methodology is essential to advance this field.

Aim: The research aims to describe histopathological characteristics in the livers of deceased patients with COVID-19 and to identify possible associations with clinical and epidemiological variables.

Methods: An observational, descriptive, cross-sectional study was conducted with 559 deceased individuals over 19 years of age who underwent minimally invasive autopsies in various Cuban hospitals between October 2021 and December 2022. Epidemiological and liver histopathological data were analyzed. A logistic regression model was used to evaluate the variables that influence the likelihood of hepatocellular necrosis.

Results: The deceased were predominantly male (n = 323, 58.0%), with a mean age of 69.4 ± 15.6 years. An acute necroinflammatory pattern was predominant, with hepatocellular necrosis observed in 486 cases (87.0%), particularly confluent necrosis in 285 cases (51.0%). Necrosis was associated with multimorbidity odds ratio (OR): 1,986 (1,055-3,737), microvacuolar steatosis (> 5%) OR = 3,348 (1,188-9,439) and steatotic liver disease OR = 8,625 (3,093-24,050). Multivariate analysis confirmed steatotic liver disease adjusted OR = 4.657; (95% confidence interval [CI]: 1.872-14.985) and cirrhosis adjusted OR = 8.294; (95% CI: 3.18-18.762) as significant predictors.

Conclusion: Hepatocellular necrosis, particularly confluent necrosis, was the predominant histopathological lesion in COVID-19 deaths in Cuba and was associated with steatotic liver disease and cirrhosis. These findings highlight the importance of monitoring liver function in patients with pre-existing liver conditions during and after SARS-CoV-2 infection.

Thirty to forty percent of patients undergoing angiography for chest pain and tightness show no abnormalities in the large coronary arteries. This phenomenon is particularly common among women, with more than 50% affected. Research has identified coronary microvascular dysfunction (CMD) as a key underlying cause; however, its pathological mechanisms remain poorly understood. In this article, we explore the relationship between CMD and coronary artery disease and summarize the current knowledge on the pathological origins of CMD, which include endothelial dysfunction, inflammation, oxidative stress, left ventricular hypertrophy and mitochondrial abnormalities. Special emphasis is placed on pathological mechanisms contributing to the higher incidence of CMD in women.

Diabetic foot ulcers (DFUs) affect over 18 million people worldwide and account for more than 70% of lower-limb amputations in the United States, emphasizing the need for effective limb-preservation strategies. This narrative review synthesizes current evidence on the algorithmic surgical management of DFUs using the reconstructive ladder to provide a practical decision guide for multidisciplinary teams. Scientific papers, society guidelines, and orthoplastic experience are integrated to outline surgical treatment recommendations, including preoperative optimization, serial debridement, wound conditioning with reconstructive adjuncts, and definitive closure techniques aligned with the reconstructive ladder. Early radical debridement combined with vascular optimization, tight glycemic control, and infection eradication forms the foundation for surgical success, while the reconstructive ladder provides the algorithm for closure, from secondary intention or tension-free primary closure for small superficial wounds, to split-thickness skin grafts for larger well-granulating defects, and to local or regional pedicled flaps for larger defects. Knowledge and application of this algorithm have the potential to reduce major amputation rates while restoring durable ambulation in complex DFU cases.

Aim: To evaluate the association between liver fibrosis, investigated by non-invasive fibrosis scores and measurement of stiffness, and diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM).

Methods: We conducted a cross-sectional, retrospective study including individuals with T2DM and hepatic steatosis who underwent a DPN examination. Liver fibrosis risk was estimated using the fibrosis-4 score (FIB-4), non-alcoholic fatty liver disease fibrosis score (NFS), aspartate transaminase (AST)/alanine transaminase (ALT) ratio, and the AST to platelet ratio index. Fibrosis was investigated using the vibration-controlled transient elastography (Fibroscan®) in a subgroup of patients. Liver stiffness measurement (LSM) ≥ 7.0 kPa defined significant fibrosis.

Results: Eighty-six T2DM subjects (mean age 59.22 ± 13.18 years; 69.8% male; DPN prevalence 43%) were included. Higher risk scores of liver fibrosis (FIB-4 and AST/ALT) in subjects with DPN compared to those without DPN were detected (FIB-4: 1.23 ± 0.66 vs. 1.63 ± 0.85; P = 0.018; AST/ALT: 0.89 ± 0.23 vs. 1.11 ± 0.61; P = 0.026). The DPN group showed higher LSM values, and the Michigan Diabetic Neuropathy Score was directly related to LSM (Rho: 0.304, P = 0.026). Moreover, a higher prevalence of alteration in vibration or reflexes was observed in subjects with LSM ≥ 7 kPa (P = 0.025 and P = 0.042, respectively). Finally, the evaluation of vibration or reflexes in individuals at high risk of liver fibrosis at FIB-4 and AST/ALT was associated with DPN (FIB-4 + abnormal vibration: P = 0.047; FIB-4 + abnormal reflexes: P = 0.013; AST/ALT + abnormal vibration: P < 0.001; AST/ALT + abnormal reflexes: P < 0.001).

Conclusion: The evaluation of vibration or reflexes would be useful in identifying DPN in T2DM with Metabolic Dysfunction-Associated Steatotic Liver Disease at high risk of fibrotic evolution.

Aim: Wearable devices have the potential to promote healthy behaviors, yet evidence on their effectiveness in pediatric populations remains scarce. This study aims to investigate the association between wearable device usage and the transition to obesity among Chinese children and adolescents, addressing critical gaps in evidence regarding optimal usage patterns and subgroup variations for obesity prevention.

Methods: Using longitudinal data from the 2019-2020 National Student Physical Health Survey (n = 5,006), this study examined associations between wearable device/mobile app usage frequency (categorized as frequent, sometimes, occasional, rare, or never use) and obesity transition among children and adolescents aged 9-18. Multivariable logistic regression models adjusted for demographics were employed, with subgroup analyses stratified by age, sex, and residence.

Results: Compared to frequent users, rare/never users showed a tendency toward higher risks of transitioning to obesity [odds ratio (OR) = 1.50, 95% confidence interval (CI): 1.04-2.18, P = 0.030]. Sometimes users had the lowest risk of physical inactivity (OR = 0.61, 95%CI: 0.51-0.73, P < 0.001), whereas never users demonstrated a higher risk of prolonged sedentary behavior (OR = 1.36, 95%CI: 1.11-1.67, P = 0.003). Subgroup analyses revealed stronger associations in rural areas (OR = 2.99, 95%CI: 1.23-7.25, P = 0.016 for overweight transition in occasional users) and boys (OR = 1.96, 95%CI: 1.05-3.68, P = 0.035 for overweight transition in rarely users).

Conclusion: Moderate, rather than frequent, use of wearable devices may optimally mitigate obesity risk in children, potentially avoiding technology fatigue from overuse. Rural-urban and gender disparities highlight the need for context-specific interventions. Wearable device use may mitigate pediatric obesity risk primarily by reducing sedentary behavior and increasing physical activity time, with optimal benefits at moderate usage frequency. These findings emphasize prioritizing usage quality over device adoption rates in public health strategies.

Metabolic dysfunction-associated steatohepatitis (MASH) represents a progressive liver disease of a rapidly increasing global prevalence, driven by intricate pathophysiological interactions within the hepatic microenvironment and systemic crosstalk between the liver and peripheral organs. This review delineates the dynamic roles of key hepatic effector cells, including hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, in disease initiation and progression, highlighting how their dysregulated intercellular communication through soluble mediators and extracellular vesicles perpetuates a vicious cycle of lipotoxicity, inflammation, and fibrosis. Furthermore, we expound on the critical involvement of extrahepatic organ networks, specifically the gut-liver, adipose-liver, and muscle-liver axes, in exacerbating hepatic metabolic dysregulation via microbial dysbiosis, aberrant adipokine secretion, and myokine imbalances. The repeated failure of highly selective, single-target therapies in clinical trials underscores the multifactorial nature of MASH pathogenesis and necessitates a paradigm shift in therapeutic strategies. We propose that future innovations should embrace two novel perspectives: first, the development of multi-target agents capable of simultaneously rectifying aberrant multicellular crosstalk within the hepatic microenvironment; and second, the modulation of dynamic interplay between the liver and other organs to restore systemic metabolic homeostasis. Ultimately, integrating such multi-target approaches with precision medicine tailored to individual genetic and phenotypic profiles holds the key to curbing the growing MASH epidemic.

Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) involves gut microbial dysbiosis and mitochondrial stress, yet the molecular link between these processes remains unclear. This study explored whether short-term L-arabinose (LA) supplementation mitigates MASLD by modulating the gut-liver axis and mitochondrial adaptive signaling.

Methods: A murine early-stage fatty liver model was established and treated orally with LA for four weeks. Gut microbial changes were assessed by 16S ribosomal RNA gene (16S rRNA) sequencing and functional prediction, while hepatic mechanisms were examined through activating transcription factor 5 (ATF5) gain- and loss-of-function experiments both in vivo and in vitro.

Results: Short-term LA administration significantly reshaped gut microbiota, enriching short-chain fatty acid-producing taxa and improving hepatic lipid metabolism. Mechanistically, LA enhanced hepatic expression of ATF5, leading to the upregulation of mitochondrial chaperone heat shock protein 60 (HSP60) and protease Lon protease 1 (LONP1), thereby initiating the mitochondrial unfolded protein response (UPRmt). Activation of UPRmt restored mitochondrial integrity, reduced oxidative stress, and attenuated hepatic lipid deposition. Silencing ATF5 abolished these protective effects, confirming its central regulatory role.

Conclusion: Short-term LA treatment alleviates MASLD by reprogramming gut microbiota and activating hepatic ATF5-mediated UPRmt signaling. These findings reveal a novel gut–mitochondrial regulatory pathway that links microbial metabolism to hepatic mitochondrial proteostasis, providing new mechanistic insight and therapeutic potential for metabolic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading and increasingly prevalent cause of chronic liver disease worldwide, with significant hepatic and extrahepatic consequences. Sex and gender are major, yet underrecognized, determinants of MASLD risk, progression, and related clinical events. This narrative review synthesizes evidence on (1) biological sex effects - including sex chromosomes, genetic variants, and the modulatory roles of estrogens and androgens on lipid metabolism, mitochondrial function, immune signalling, and fibrogenesis - and (2) gendered socio-behavioral influences such as diet, physical activity, alcohol and tobacco use, health-seeking behavior, pregnancy and lactation, and gender-affirming hormone therapy. We highlight sex differences in metabolic phenotypes (fat distribution, insulin resistance, dyslipidemia, and hypertension), emerging sex-specific gene-microbiome interactions in the gut-liver axis, and sex-dependent patterns of extrahepatic comorbidity (cardiovascular disease, chronic kidney disease, and selected cancers). Evidence also suggests that commonly used diagnostic tools and predictive algorithms - including non-invasive fibrosis scores and machine-learning models - may misclassify risk if sex and hormonal status are not considered, and that pharmacologic, surgical, and hormone-based therapies exhibit preliminary sex-specific effects. Based on these observations, we propose a conceptual framework in which sex and gender, individually and interactively, shape the MASLD burden. Critical knowledge gaps remain, particularly for premenopausal women, transgender, and non-binary populations. Incorporating sex and gender into study design, diagnostics, risk stratification, and clinical trials is essential to advance precision prevention and equitable care for MASLD.

Aim: The prevalence of obesity among Chinese children and adolescents has been widely reported, but incidence data remain scarce. This study examined the prevalence and incidence of obesity in Guangdong amid ongoing economic and demographic transitions.

Methods: This study used data from the Surveillance for Common Diseases and Health Risk Factors in Students in Guangdong Province (2019-2022). We calculated the prevalence (n = 117,862) and incidence (n = 108,043) of obesity among children and adolescents aged 6-19 years, stratified by sex, age, educational level, ethnicity, and residence.

Results: The baseline crude prevalence was 8.33% [95% confidence interval (CI): 8.17%, 8.49%] for obesity and 10.86% (95%CI: 10.69%, 11.04%) for overweight. The crude prevalence of obesity increased from 7.41% (95%CI: 7.17%, 7.65%) in 2019 to 9.10% (95%CI: 8.89%, 9.31%) in 2022. The crude cumulative incidence was 3.03%, with an incidence density rate of 19.32 cases per 1,000 person-years (PYs). Incidence density rates declined from 2019-2020 (27.85 cases per 1,000 PYs) to 2020-2021 (19.01 cases per 1,000 PYs), followed by a slight, non-significant increase from 2020-2021 to 2021-2022 (19.74 cases per 1,000 PYs). Both the prevalence and incidence of overweight and obesity were higher in younger children and in boys than in their respective counterparts.

Conclusion: Our longitudinal study (2019-2022) in Guangdong Province showed a persistent increase in obesity prevalence, despite fluctuations in incidence among children and adolescents. The upward trend, particularly pronounced in younger children and boys, highlights the urgent need for targeted public health interventions.

Aim: Sensitive periods in child development are times when certain exposures may exert greater influences on health outcomes. The exposure to overweight/obesity and its cumulative effect during children’s sensitive periods may be associated with a higher risk of high blood pressure (HBP) in childhood.

Methods: A total of 522 boys and 534 girls (mean age: 9.6 years old, standard deviation: 0.6) from the birth cohort were selected for subsequent analysis. The curves of body mass index Z-score were generated by mixed-effect models. The statistically significant relative risk (RR) values of the first derivatives of the curves, evaluated at 0.5 year intervals, were used to identify the sensitive period. The area under the curve was employed to measure the cumulative exposure to overweight/obesity. Binary logistic regression model was used to investigate the association between the cumulative effect and risk of HBP in children.

Results: The sensitive periods identified were 2.5-5.5 years in boys and 7.0-8.5 years in girls. During these sensitive periods, the cumulative effect [RR: 1.12, 95% confidence interval (CI): 1.07-1.17, P < 0.001] and the average cumulative effect (RR: 1.21, 95%CI: 1.16-1.28, P < 0.001) of overweight/obesity exerted a greater impact on the risk of HBP than during periods outside the sensitive periods (cumulative effect: RR: 1.01, 95%CI: 1.00-1.03, P = 0.036; average cumulative effect: RR: 1.02, 95%CI: 1.00-1.03, P = 0.049).

Conclusion: This study identified the sensitive periods during which overweight/obesity influences the risk of HBP in children aged 9-10 years and demonstrated the greater cumulative effect of overweight/obesity on the elevated risk of HBP.

The mechanisms of hepatocellular injury in steatotic liver disease (SLD) and cholestasis remain unclear. One hypothesis is that hepatocytes are exposed to unconjugated toxic bile acids due to damage to the biliary mucus layer. Loss of mucus phosphatidylcholine (PC) impairs sealing, allowing unconjugated bile acids secreted in bile to be reabsorbed through leaky biliary epithelium and recirculated via portal blood to hepatocytes (cholehepatic shunting). Augmenting mucus PC could block cholangiocellular uptake of these bile acids and consequent hepatocyte exposure, which is postulated to be achieved through PC supplementation. Medium-chain PC (MCPC), secreted by multidrug resistance protein 3 (MDR3) across the canalicular membrane into bile, does not form micelles with bile acids, thus remaining available to enrich the mucus PC layer. Hepatocellular MCPC for biliary secretion can be increased by direct MCPC delivery or hepatic remodeling of oral long-chain PC provided together with medium-chain triglycerides. The reassembled breakdown products yield MCPC, helping mitigate hepatocellular injury in cholestatic states, including SLD.

Aim: Estimated pulse wave velocity (ePWV) is a surrogate marker of arterial stiffness and has been reported as an important risk factor for cardiovascular, kidney, and metabolic disorders. However, the associations of ePWV with cardiovascular-kidney-metabolic (CKM) multimorbidity are limited. We aim to examine the association between ePWV and CKM stages among adults in the United States (US).

Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2018. CKM multimorbidity was defined as the concurrent presence of subclinical or clinical cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic disorders. Participants were classified into five CKM stages according to the clinical severity of these coexisting conditions. ePWV was calculated using a validated formula based on age and blood pressure. All analyses incorporated survey weights, strata, and primary sampling units to account for NHANES’s complex multistage sampling design. Survey-weighted multinomial logistic regression models were applied to evaluate the associations between ePWV and CKM stages.

Results: A total of 21,397 adults from the US aged 20 years or older were included in the analysis. Overall, 17.9% of participants (n = 5,406) had an ePWV ≥ 10 m/s. Higher ePWV was associated with more advanced CKM stages. In fully adjusted models, each 1 m/s increase in ePWV was associated with higher odds of CKM stage 1 [odds ratios (ORs) 1.50, 95% confidence interval (CI) 1.36-1.66], stage 2 (OR 3.04, 95% CI 2.73-3.38), stage 3 (OR 8.08, 95% CI 7.12-9.16), and stage 4 (OR 4.49, 95% CI 4.01-5.03), compared with CKM stage 0. Significant interactions by sex and ethnicity were observed. The associations between ePWV and advanced CKM stages (stages 3-4) were stronger in males than in females, and Black individuals had higher odds of advanced CKM stages compared with White or Mexican individuals (all P for interaction < 0.05).

Conclusions: Greater arterial stiffness, as indicated by higher ePWV, was associated with an increased risk of CKM multimorbidity after adjustment for sociodemographic characteristics, lifestyle factors, and CKM-related risk factors.

Aim: Although the association between biological age (BA) and liver dysfunction is well-established, epidemiological evidence on the relationship between BA acceleration and cirrhosis risk in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remains limited.

Methods: This study included 89,935 individuals with MASLD from the UK Biobank. We used Klemera-Doubal method-BA (KDM-BA), phenotypic age (PhenoAge) and leukocyte telomere length (LTL) as BA indicators. Twelve genetic variants were used to construct polygenic risk scores (PRS). Multivariable Cox proportional hazards models were employed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cirrhosis incidence.

Results: During a median follow-up of 12.05 years, 519 individuals developed cirrhosis. Acceleration in PhenoAge and KDM-BA was associated with a 39% (HR 1.39, 95%CI: 1.32-1.47) and 12% (HR 1.12, 95%CI: 1.03-1.22) higher risk of incident cirrhosis, respectively. Longer LTL was associated with a lower risk of cirrhosis (HR 0.84, 95%CI: 0.77-0.91). Participants with the greatest BA acceleration and highest PRS exhibited the highest risk of cirrhosis. Additionally, participants at a high genetic risk level had the greatest 10-year absolute risk reduction of cirrhosis (17.74 per 1,000 person-years) if their PhenoAge acceleration decreased.

Conclusion: Our findings demonstrate that alleviating biological aging in individuals with MASLD is important for preventing cirrhosis and could mitigate the adverse effects of high genetic risk.

Aim: Wilson’s disease (WD) primarily manifests in hepatic and neurological symptoms. This study aims to integrate multimodal neuroimaging and hepatic imaging analysis to provide novel insights into the diagnosis and severity assessment of WD.

Methods: This study recruited patients diagnosed with hepatic-type WD (HWD), neurological-type WD (NWD), and healthy controls (HCs). All participants underwent both brain and liver magnetic resonance imaging (MRI) scanning. The quantitative susceptibility mapping (QSM) values, volumes of different brain regions, fat content, and iron quantification in liver regions of interest (ROIs) were compared and analyzed across groups. The diagnostic biomarkers were identified by LASSO (Least Absolute Shrinkage and Selection Operator) regression, and their diagnostic value was evaluated using receiver operating characteristic (ROC) analysis. In addition, the correlation between the severity of neurological symptoms and imaging biomarkers was analyzed.

Results: A total of 38 subjects were included in this study, comprising 17 cases of HWD, 10 NWD, and 11 HCs. Compared to HCs, the WD group, especially NWD, exhibited significant iron deposition in liver segments. Additionally, QSM values were significantly increased. The regional brain volumes were significantly reduced. The ROC curve demonstrates that the combination of brain QSM values and volumes selected exhibits strong discriminatory power in distinguishing between WD vs. HCs, NWD vs. HCs, HWD vs. HCs, and NWD vs. HWD.

Conclusion: Iron deposition in the liver and brain, as well as the extent of regional brain atrophy, may serve as predictive markers for the onset of WD, particularly NWD. All suspected and confirmed WD patients, regardless of NWD or HWD, should undergo brain and liver MRI for diagnostic evaluation and follow-up assessments.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly 1.5 billion adults worldwide. It is closely associated with type 2 diabetes mellitus and obesity. Longer duration of MASLD increases risk of progression to metabolic dysfunction-associated steatohepatitis (MASH, the progressive form of MASLD that requires pharmacological therapy), cirrhosis and hepatocellular carcinoma, as well as development of cardiovascular complications. Despite the need for MASH pharmacologic intervention, several studies on new investigational compounds have failed, with only Resmetirom and Semaglutide recently conditionally approved by the Food and Drug Administration (FDA). The role of incretins may be more critical in the early phase of MASH development, but integration with drugs that directly target the liver may represent the winning strategy. The armamentarium of drugs for MASH is rapidly expanding, and several promising drugs are under investigation in phase 2 of development. Integrating fibrosis stage-specific combination therapies targeting different steps of the complex pathogenic mechanism of MASLD/MASH may lead to successful treatment rates larger than the currently obtained 25%-30%. The effects of both FDA-approved compounds (Resmetirom and Semaglutide) on clinical outcomes remain to be shown and will not be available before the conclusion of the respective outcome studies in 2027 and 2028.