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Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disease globally, driven by rising obesity, metabolic syndrome (MetS), and type 2 diabetes mellitus (T2DM). This study evaluates the global, regional, and national burden of MAFLD-related diseases from 1990 to 2021 and projects future trends. Data were sourced from the Global Burden of Disease (GBD) 2021 database, including estimates for the incidence, prevalence, mortality, and disability-adjusted life years (DALYs) associated with MAFLD, MAFLD-related cirrhosis, and MASH-related liver cancer. Countries were classified into 21 regions and five socio-demographic index (SDI) quintiles to analyze health disparities. Decomposition analyses assessed the contributions of population growth, aging, and epidemiological shifts. Future trends were modeled using the Bayesian Age-Period-Cohort (BAPC) framework. In 2021, approximately 1.27 billion MAFLD cases were reported globally, with an age-standardized prevalence rate (ASPR) of 15,018 per 100,000. The highest incidence occurred in South and East Asia. Mortality reached 138,328 cases for MAFLD and 97,403 for MAFLD-related cirrhosis. Decomposition analyses highlighted population growth and aging as key drivers. BAPC projections indicate a continued rise in MAFLD burden, particularly in low- and middle-income countries. This study underscores the increasing global burden of MAFLD and its complications. Targeted public health interventions focusing on prevention and early management are urgently needed to mitigate future impacts.

Due to their bacterial ancestry, many components of mitochondria share structural similarities with bacteria. Release of molecular danger signals from injured cell mitochondria (mitochondria-derived damage-associated molecular patterns, mito-DAMPs) triggers a potent inflammatory response, but their role in fibrosis is unknown. Using liver fibrosis resistant/susceptible mouse strain system, we demonstrate that mito-DAMPs released from injured hepatocyte mitochondria (with mtDNA as major active component) directly activate hepatic stellate cells, the fibrogenic cell in the liver, and drive liver scarring. The release of mito-DAMPs is controlled by efferocytosis of dying hepatocytes by phagocytic resident liver macrophages and infiltrating Gr-1(+) myeloid cells. Circulating mito-DAMPs are markedly increased in human patients with non-alcoholic steatohepatitis (NASH) and significant liver fibrosis. Our study identifies specific pathway driving liver fibrosis, with important diagnostic and therapeutic implications. Targeting mito-DAMP release from hepatocytes and/or modulating the phagocytic function of macrophages represents a promising antifibrotic strategy. Progressive fibrosis is a driver of morbidity and mortality in many chronic liver diseases, but the underlying mechanisms are incompletely understood. Here, the authors show that mitochondria-derived damage-associated molecular patterns are released from injured hepatocytes and can trigger fibrogenic activation of hepatic stellate cells.

The nuclear receptor (NR) superfamily consists of the orphan NR subgroup NR4A, of which Nur77, an immediate early response gene, plays a crucial role in liver physiology and pathophysiology. Nur77 acts as a transcription factor with genomic and non-genomic activities. This review summarises Nur77’s role in liver diseases and its potential as a therapeutic target, as numerous studies have explored the diverse therapeutic implications of targeting Nur77 across different liver diseases.

The incidence of NAFLD, which increases the risk of liver cancer, is increasing to epidemic proportions. This Review outlines the correlations between liver cancer and NAFLD-related cirrhosis, and the role of the metabolic syndrome in the development of liver cancer. Advances in understanding the progression of NAFLD to hepatocellular carcinoma from preclinical models will also be discussed. NAFLD affects a large proportion of the US population and its incidence and prevalence are increasing to epidemic proportions around the world. As with other liver diseases that cause cirrhosis, NAFLD increases the risk of liver cancer, a disease with poor outcomes and limited therapeutic options. The incidences of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma are also rising, and HCC is now the leading cause of obesity-related cancer deaths in middle-aged men in the USA. In this Review, we summarize the correlations between liver cancer and NAFLD-related cirrhosis, and the role of the metabolic syndrome in the development of liver cancer from diverse aetiologies, including HCV-mediated cirrhosis. Recent advances in understanding the progression of NAFLD to HCC from preclinical models will also be discussed. Targeted genetic manipulation of certain metabolic or stress-response pathways, including one-carbon metabolism, NF-κB, PTEN and microRNAs, has been valuable in elucidating the pathways that regulate carcinogenesis in NAFLD. Although tremendous advances have occurred in the identification of diagnostic and therapeutic opportunities to reduce the progression of NAFLD, considerable gaps in our knowledge remain with regard to the mechanisms by which NAFLD and its risk factors promote liver cancer. Key Points NAFLD is strongly associated with obesity and the metabolic syndrome; as with these conditions, the incidence and prevalence of NAFLD are increasing to epidemic proportions Similar to other liver diseases that cause cirrhosis, NAFLD increases the risk of liver cancer Liver cancers generally arise after NAFLD-related cirrhosis has developed, but can also occur in patients with NAFLD before cirrhosis ensues The metabolic syndrome increases the risk of liver cancer in individuals with other liver diseases (for example, cirrhosis caused by chronic HCV infection) Targeted genetic manipulation of certain metabolic or stress-response pathways causes NAFLD and liver cancer in experimental animal models A subset of human liver cancers has a gene expression profile indicative of defective intermediary metabolism

Microphysiology systems (MPS), also called organs-on-chips and tissue chips, are miniaturized functional units of organs constructed with multiple cell types under a variety of physical and biochemical environmental cues that complement animal models as part of a new paradigm of drug discovery and development. Biomimetic human liver MPS have evolved from simpler 2D cell models, spheroids and organoids to address the increasing need to understand patient-specific mechanisms of complex and rare diseases, the response to therapeutic treatments, and the absorption, distribution, metabolism, excretion and toxicity of potential therapeutics. The parallel development and application of transdisciplinary technologies, including microfluidic devices, bioprinting, engineered matrix materials, defined physiological and pathophysiological media, patient-derived primary cells, and pluripotent stem cells as well as synthetic biology to engineer cell genes and functions, have created the potential to produce patient-specific, biomimetic MPS for detailed mechanistic studies. It is projected that success in the development and maturation of patient-derived MPS with known genotypes and fully matured adult phenotypes will lead to advanced applications in precision medicine. In this Review, we examine human biomimetic liver MPS that are designed to recapitulate the liver acinus structure and functions to enhance our knowledge of the mechanisms of disease progression and of the absorption, distribution, metabolism, excretion and toxicity of therapeutic candidates and drugs as well as to evaluate their mechanisms of action and their application in precision medicine and preclinical trials. Human microphysiology systems (MPS) have evolved as experimental model systems. This Review explores these so-called organ-on-a-chip systems and the role of biomimetic human liver MPS in drug development and precision medicine, providing insights into their design and use as models of liver physiology and disease. Key points Liver in vitro experimental models have a long history involving the use of 2D and 3D models that continue to have valuable roles in our understanding of liver physiology and pathophysiology. Human microphysiology systems (MPS) have evolved from simple cell-based experimental models and have the potential to meet the need for human experimental models for basic biomedical research and the development of therapeutics. Human biomimetic liver MPS (HBL-MPS) aim to improve the efficiency of developing biomarkers, repurposed drugs and novel therapeutics by maximally recapitulating the structure and functions of the liver acinus. HBL-MPS are evolving based either on liver organoids derived from patient cells that self-assemble and differentiate or on the directed assembly or bioprinting of matrix materials and cells into microfluidic devices. Organoid-derived MPS and structured MPS are next-generation HBL-MPS that are projected to enable applications of precision medicine, including preclinical trials, either as stand-alone liver models or as coupled, multi-organ MPS.

Recompensation has gained increasing attention in the field of cirrhosis, particularly in chronic liver disease with a definite aetiology. The current global prevalence of obesity and nonalcoholic fatty liver disease (NAFLD) is increasing, but there is currently a lack of a clear definition for recompensation in NAFLD-related cirrhosis. Here, we provide an up-to-date perspective on the natural history of NAFLD, emphasizing the reversible nature of the disease, summarizing possible mechanisms underlying recompensation in NAFLD, discussing challenges that need to be addressed and outlining future research directions in the field. Recompensation is a promising goal in patients with NAFLD-related cirrhosis, and further studies are needed to explore its underlying mechanisms and uncover its clinical features. Cirrhosis recompensation is gradually gaining traction, but a definition for recompensation in nonalcoholic fatty liver disease (NAFLD)-related cirrhosis is currently lacking. This Perspective provides an overview of the natural history of NAFLD and discusses NAFLD-related cirrhosis recompensation.

The canonical Wnt–β-catenin pathway is a complex, evolutionarily conserved signalling mechanism that regulates fundamental physiological and pathological processes. Wnt–β-catenin signalling tightly controls embryogenesis, including hepatobiliary development, maturation and zonation. In the mature healthy liver, the Wnt–β-catenin pathway is mostly inactive but can become re-activated during cell renewal and/or regenerative processes, as well as in certain pathological conditions, diseases, pre-malignant conditions and cancer. In hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumours in adults, Wnt–β-catenin signalling is frequently hyperactivated and promotes tumour growth and dissemination. A substantial proportion of liver tumours (mainly HCC and, to a lesser extent, CCA) have mutations in genes encoding key components of the Wnt–β-catenin signalling pathway. Likewise, hepatoblastoma, the most common paediatric liver cancer, is characterized by Wnt–β-catenin activation, mostly as a result of β-catenin mutations. In this Review, we discuss the most relevant molecular mechanisms of action and regulation of Wnt–β-catenin signalling in liver development and pathophysiology. Moreover, we highlight important preclinical and clinical studies and future directions in basic and clinical research.

Hepatitis C virus (HCV) is a worldwide health hazard, and in chronic form (nowadays affecting 50 million people – World Health Organization data) can be lethal. To forestall it, preventive screening is a mandatory approach. Since 2021, Italy conducts a national-wide screening program to eliminate the virus from its population. The team perfected an innovative method throughout the period between 2022 and 2023, to answer that medical necessity and map HCV genotypes. The medical protocol has introduced a dedicated double invitation model for the adherents, with consequential pre-prepared medical consumables allocated. The population was divided in three separate groups: born between 1969 and 1989, addiction services, and prison. Two screening levels were carried out: anti-HCV antibodies (indirect chemiluminescence immunoassay) and quantitative HCV RNA reverse transcription. 51,283 adherents were registered: 447 resulted positive to the first screening round, and 88 to the second (393 and 77 patients respectively from population born between 1969 and 1989). The medical protocol introduced allowed to substantially increase patients and medical staff compliance to HCV screening (adherence: 51.83%, the highest in Italy). HCV genotypes’ distribution was mapped by patients’ age, biological sex and origin over five groups comprehending subtypes 1a(35.06% of the positive population), 1b(27.27%), 2a/2c(10.39%), 3a(22.08%), 4a/4c/4d(5.19%).

Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and ≥10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants ( n  = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg), −82.4% (12 mg) and +0.3% (placebo) (all P  < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 . Phase 2 clinical trial results show that retatrutide, a triple agonist of the GIP, GLP-1 and glucagon receptors, results in up to 82% reduction in liver fat.

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2 + CD9 + subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1 + and PLVAP + endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα + collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis. Single-cell RNA sequencing is used to characterize and compare the functional diversity of cells from liver biopsies of human scarred and normal liver, and identifies markers for scar-associated macrophages and endothelial cells.