The pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) extends beyond intrinsic hepatic metabolic defects, involving critical bidirectional communication between the liver and the central nervous system—termed the liver-nervous system axis. This review proposes that dysregulation of this axis, characterised by sympathetic overactivation and parasympathetic hypofunction, is a central driver of MASLD onset and progression. We review the ‘brain-to-liver’ and ‘liver-to-brain’ signalling pathways, highlighting how their disruption forms a reciprocally detrimental feedback loop that exacerbates systemic metabolic disturbance. Furthermore, we summarise preclinical and clinical evidence to demonstrate that targeting this axis, through pharmacological, neuromodulatory or behavioural interventions, represents a promising therapeutic frontier. By moving beyond traditional paradigms, this approach offers a novel framework for the mechanism-based management of MASLD across disease stages.

Alcohol-associated liver disease (ALD) is a leading cause of liver-related deaths in the United States and worldwide, occurring in persons with alcohol use disorder (AUD). Effective treatment of AUD is essential to curtail the progression of ALD and/or reverse the disease course, yet there is a paucity of information on care models for the concomitant treatment of AUD in persons with ALD, particularly when liver transplant is not imminent or warranted. Here, we reviewed existing literature on care models for the concomitant treatment of ALD and AUD among individuals not undergoing liver transplant evaluation or consideration. A comprehensive search of electronic databases including Cochrane Library, CINAHL, Ovid MEDLINE, Ovid Embase, Scopus, Google Scholar, PubMed, and Web of Science Core Collection from inception to July 2024 was conducted to identify original studies reporting care for both ALD and AUD in persons not undergoing liver transplant evaluation or consideration. From the 1146 publications identified, 43 studies were selected for further review, of which three articles were selected for data charting and inclusion in the review. Concomitant treatment of ALD and AUD were implemented both within inpatient and outpatient settings, with multidisciplinary care teams typically involving hepatology and addiction medicine and/or addiction psychiatry. One study showed that attention and care for AUD led to improvement in liver disease and a decrease in emergency department visits and frequency of hospitalization. The studies reviewed suggest that concomitant care for ALD and AUD in the nontransplant setting may improve outcomes for some patients. The limited number of studies highlights the need for more prospective and longitudinal studies evaluating concomitant treatment, especially in persons for whom liver transplant may not be an option or a consideration.

Glucagon-like peptide 1 receptor (GLP-1R) agonists are used along with ethanol consumption, but their interactions are not understood. Our aim was to determine the effects of GLP-1R agonism on the liver in mouse models of high ethanol consumption. We identified that GLP-1R agonism reduced ethanol consumption, mitigated ethanol-induced upregulation of several liver metabolizing enzymes, including Cyp2e1 and also reduced Cyp2e1 independent of ethanol intake. As expected from a reduction in Cyp2e1, GLP-1R agonism resulted in increased blood ethanol levels. This occurred after a single dose of ethanol when given by gavage, and by the intraperitoneal route. This suggests that GLP-1R agonism can reduce ethanol-mediated hepatotoxicity despite continued ethanol consumption and elevate blood alcohol levels.

Metabolic dysfunction and alcohol-associated liver disease (MetALD) is a recently implemented nomenclature and disease terminology for patients with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol. MetALD is diagnosed in individuals who have at least one metabolic risk factor (such as obesity, type 2 diabetes mellitus, hypertension, etc) and consume 140–350 g/week of alcohol for women or 210–420 g/week for men. Conversely, alcohol-associated liver disease is diagnosed in individuals who consume >350 g/week of alcohol for women and >420 g/week for men. MetALD represents a heterogeneous spectrum of liver disease, with variations in clinical presentation and severity driven by differences in metabolic profiles, drinking patterns and individual susceptibility. Alcohol and metabolic risk factors are thought to act synergistically to accelerate steatohepatitis, fibrosis and hepatocellular carcinoma. However, the precise mechanisms underlying liver injury in MetALD still remain poorly understood. In this comprehensive review, we summarise the current definition, diagnostic criteria and clinical management of MetALD. We also discuss emerging insights into understanding its pathogenesis, examine relevant experimental models and highlight future challenges and research priorities in this evolving field.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a prominent global health concern associated with high risk of metabolic syndrome, and has impacted a substantial segment of the population. The disease spectrum ranges from simple fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma (HCC) and is increasingly becoming a prevalent indication for liver transplantation. The existing therapeutic options for NAFLD, NASH, and HCC are limited, underscoring the urgent need for innovative treatment strategies. Insights into gene expression, particularly RNA modifications such as N6 methyladenosine (m6A), hold promising avenues for interventions. These modifications play integral roles in RNA metabolism and cellular functions, encompassing the entire NAFLD-NASH-HCC progression. This review will encompass recent insights on diverse RNA modifications, including m6A, pseudouridine (ψ), N1-methyladenosine (m1A), and 5-methylcytidine (m5C) across various RNA species. It will uncover their significance in crucial aspects such as steatosis, inflammation, fibrosis, and tumorigenesis. Furthermore, prospective research directions and therapeutic implications will be explored, advancing our comprehensive understanding of the intricate interconnected nature of these pathological conditions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.

BACKGROUND:Alcohol-associated hepatitis (AH) is a subtype of alcohol-associated liver disease (ALD) resulting in severe acute liver inflammation. This study aims to examine longitudinal trends in mortality from AH in the United States (US) from 1999 to 2020, stratifying the data by sex, age, and racial/ethnic groups. METHODS:We performed a cross-sectional study using data from the US Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (WONDER) to determine annual AH-related mortality rates (MR) in adults ≥21 years between 1999 and 2020. Data were stratified by sex, race, and 10-year age groups. Considering 1999 as baseline, mortality rate ratio (MRR) was calculated to characterize the MR in a particular year compared to baseline. Joinpoint regression analysis was conducted to characterize year-wise log-linear time calendar trends in MR. RESULTS:From 1999 through 2020, AH-related deaths doubled from 0.5 per 100,000 (95% CI 0.5 to 0.6) to 1.1 per 100,000 (95% CI 1.1 to 1.2). While mortality rates for males doubled from 0.8 per 100,000 (95% CI 0.7 to 0.8) to 1.5 per 100,000 (95% CI 1.4 to 1.6), mortality rates for females almost tripled from 0.3 per 100,000 (9%% CI 0.3 to 0.4) to 0.8 per 100,000 (95% CI 0.7 to 0.8). The steepest increase in AH-related deaths from 1999 to 2020 were among American Indians/Alaska Natives and young adults 25-34 years, and particularly young adult females. CONCLUSIONS:Over the past two decades, overall AH-related mortality in the US has doubled. The steepest increase in AH-related mortality was noted among American Indians/Alaska Natives and young adults, particularly young adult females. Education and prevention efforts should target these high-risk populations, and studies aimed at elucidating biological and sociodemographic factors resulting in the differential rise in mortality are warranted.

Lipids are important in multiple cellular functions, with most having structural or energy storage roles. However, a small fraction of lipids exert bioactive roles through binding to G protein-coupled receptors and induce a plethora of processes including cell proliferation, differentiation, growth, migration, apoptosis, senescence and survival. Bioactive signalling lipids are potent modulators of metabolism and energy homeostasis, inflammation, tissue repair and malignant transformation. All these events are involved in the initiation and progression of chronic liver diseases. In this review, we focus specifically on the roles of bioactive lipids derived from phospholipids (lyso-phospholipids) and poly-unsaturated fatty acids (eicosanoids, pro-resolving lipid mediators and endocannabinoids) in prevalent chronic liver diseases (alcohol-associated liver disease, non-alcoholic fatty liver disease, viral hepatitis and hepatocellular carcinoma). We discuss the balance between pathogenic and beneficial bioactive lipids as well as potential therapeutic targets related to the agonism or antagonism of their receptors.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) and resultant steatohepatitis (MASH) have been linked to psychiatric comorbidities. The treatment of MASLD/MASH primarily relies upon weight loss. We aimed to determine whether metabolic and hepatic outcomes in MASLD/MASH patients were significantly different with the presence of comorbid psychiatric disease in an interdisciplinary clinic that integrates weight management and hepatology care. Methods: We conducted a retrospective cohort study comparing outcomes of MASLD/MASH patients aged ≥ 18 years with mood and/or anxiety disorders to those without followed for 1 year. The primary outcome was reaching 7% total body weight loss (TBWL) at 12 months with logistic regression models used to identify treatments which predicted 7% TBWL. Secondary outcomes were noninvasive assessment of steatohepatitis improvement, including change in ALT and FIB-4 scoring. Results: Of 567 patients with MASLD/MASH, 366 (64.6%) had a comorbid mood and/or anxiety disorder. Presence of comorbid psychiatric disease was not a significant predictor of weight loss or any of the secondary outcome measures at 12 months. Significant predictors of achieving 7% TBWL at 12 months among all patients with MASLD/MASH included semaglutide, phentermine-topiramate, and bariatric surgery. Significant predictors of achieving 7% TBWL at 12 months in patients with MASLD/MASH and a psychiatric comorbidity included semaglutide, topiramate, phentermine-topiramate, and bariatric surgery. Both groups experienced similar improvements in hepatic outcomes. Conclusions: Our findings suggest that obesity management in patients with MASLD performs similarly in the presence of comorbid psychiatric disorders. Topiramate and phentermine may be particularly effective in this patient population yet are underutilized in hepatology practices.

We assessed in vivo rates of hepatic mitochondrial oxidation, gluconeogenesis, and b-hydroxybutyrate (b-OHB) turnover by positional isotopomer NMR tracer analysis (PINTA) in individuals with metabolic-dysfunction-associated steatotic liver (MASL) (fatty liver) and MASL disease (MASLD) (steatohepatitis) compared with BMI-matched control participants with no hepatic steatosis. Hepatic fat content was quantified by localized 1H magnetic resonance spectroscopy (MRS). We found that in vivo rates of hepatic mitochondrial oxidation were unaltered in the MASL and MASLD groups compared with the control group. A physiological increase in plasma glucagon concentrations increased in vivo rates of hepatic mitochondrial oxidation by 50%-75% in individuals with and without MASL and increased rates of glucose production by '50% in the MASL group, which could be attributed in part to an '30% increase in rates of mitochondrial pyruvate carboxylase flux. These results demonstrate that (1) rates of hepatic mitochondrial oxidation are not substantially altered in individuals with MASL and MASLD and (2) glucagon increases rates of hepatic mitochondrial oxidation.

BACKGROUND AND AIMS:Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for HCC. Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy. APPROACH AND RESULTS:We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 patients with HCC, in which 17 patients received anti-programmed cell death-1 (PD-1) therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly, 60 publicly available multiomics data sets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mouse model ls. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies. CONCLUSIONS:We identified 3 FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.

Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), creating an unmet need to identify noninvasive biomarkers for AH. In murine models, complement contributes to ethanol-induced liver injury. Therefore, we hypothesized that complement proteins could be rational diagnostic/prognostic biomarkers in AH. Here, we performed a comparative analysis of data derived from human hepatic and serum proteome to identify and characterize complement protein signatures in severe AH (sAH). The quantity of multiple complement proteins was perturbed in liver and serum proteome of patients with sAH. Multiple complement proteins differentiated patients with sAH from those with alcohol cirrhosis (AC) or alcohol use disorder (AUD) and healthy controls (HCs). Serum collectin 11 and C1q binding protein were strongly associated with sAH and exhibited good discriminatory performance among patients with sAH, AC, or AUD and HCs. Furthermore, complement component receptor 1-like protein was negatively associated with pro-inflammatory cytokines. Additionally, lower serum MBL associated serine protease 1 and coagulation factor II independently predicted 90-day mortality. In summary, meta-analysis of proteomic profiles from liver and circulation revealed complement protein signatures of sAH, highlighting a complex perturbation of complement and identifying potential diagnostic and prognostic biomarkers for patients with sAH.

Chronic liver disease leads to hepatocellular injury that triggers a pro-inflammatory state in several parenchymal and non-parenchymal hepatic cell types, ultimately resulting in liver fibrosis, cirrhosis, portal hypertension and liver failure. Thus, an improved understanding of inflammasomes - as key molecular drivers of liver injury - may result in the development of novel diagnostic or prognostic biomarkers and effective therapeutics. In liver disease, innate immune cells respond to hepatic insults by activating cell-intrinsic inflammasomes via toll-like receptors and NF-κB, and by releasing pro-inflammatory cytokines (such as IL-1β, IL-18, TNF-α and IL-6). Subsequently, cells of the adaptive immune system are recruited to fuel hepatic inflammation and hepatic parenchymal cells may undergo gasdermin D-mediated programmed cell death, termed pyroptosis. With liver disease progression, there is a shift towards a type 2 inflammatory response, which promotes tissue repair but also fibrogenesis. Inflammasome activation may also occur at extrahepatic sites, such as the white adipose tissue in MASH (metabolic dysfunction-associated steatohepatitis). In end-stage liver disease, flares of inflammation (e.g., in severe alcohol-related hepatitis) that spark on a dysfunctional immune system, contribute to inflammasome-mediated liver injury and potentially result in organ dysfunction/failure, as seen in ACLF (acute-on-chronic liver failure). This review provides an overview of current concepts regarding inflammasome activation in liver disease progression, with a focus on related biomarkers and therapeutic approaches that are being developed for patients with liver disease.

Abstract Background Fermented soy products have shown to possess inhibitory effects on prostate cancer (PCa). We evaluated the effect of a fermented soy beverage (Q-Can®), containing medium-chain triglycerides, ketones and soy isoflavones, among men with localized PCa prior to radical prostatectomy. Methods We conducted a placebo-controlled, double-blind randomized trial of Q-Can®. Stratified randomization (Cancer of the Prostate Risk Assessment (CAPRA) score at diagnosis) was used to assign patients to receive Q-Can® or placebo for 2–5 weeks before RP. Primary endpoint was change in serum PSA from baseline to end-of-study. We assessed changes in other clinical and pathologic endpoints. The primary ITT analysis compared PSA at end-of-study between randomization arms using repeated measures linear mixed model incorporating baseline CAPRA risk strata. Results We randomized 19 patients, 16 were eligible for analysis of the primary outcome. Mean age at enrollment was 61, 9(56.2%) were classified as low and intermediate risk, and 7(43.8%) high CAPRA risk. Among patients who received Q-Can®, mean PSA at baseline and end-of-study was 8.98(standard deviation, SD 4.07) and 8.02ng/mL(SD 3.99) compared with 8.66(SD 2.71) to 9.53ng/mL(SD 3.03), respectively, (Difference baseline – end-of-study, p = 0.36). There were no significant differences in Gleason score, clinical stage, surgical margin status, or CAPRA score between treatment arms (p > 0.05), and no significant differences between treatment arms in end-of-study or change in lipids, testosterone and FACT-P scores (p > 0.05). Conclusions Short exposure to Q-Can® among patients with localized PCa was not associated with changes in PSA levels, PCa characteristics including grade and stage or serum testosterone. Due to early termination from inability to recruit, study power, was not achieved.