GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis.

Background & Aims: Cellular senescence is characterized by the loss of proliferative capacity, cell cycle arrest, and the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP). Senescence is frequently present in advanced chronic liver diseases; however, the impact of hepatocellular senescence in alcohol-associated liver disease (ALD) progression and alcohol-associated hepatitis (AH) is poorly understood.

Methods: Senescence was evaluated in transcriptomic data from patients at different ALD stages: advanced fibrosis (n = 10), cirrhosis (n = 10), and AH (n = 29).

Deep-Learning Driven Identification of Novel Antimicrobial Peptides.

In this study, we report the identification of novel antimicrobial peptides (AMPs) via a machine learning-driven pipeline. Short Trp-rich peptide sequences were obtained using the HydrAMP deep learning (DL) algorithm, followed by the in silico screening for antimicrobial activity via the AMPlify DL model. Three candidates, namely AMP1, AMP2, and AMP3, were selected for synthesis and experimental validation.

Patient-derived liver organoids recapitulate liver epithelial heterogeneity and enable precision modeling of alcohol-related liver disease.

Background & Aims: Alcohol-associated liver disease (ALD) is a major cause of liver disease worldwide with scarce therapeutic options. Animal models poorly recapitulate advanced ALD precluding the development of new treatments. Organoids have emerged as a powerful human-based preclinical tool.

Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis.

Defining the trajectory of cells during differentiation and disease is key for uncovering the mechanisms driving cell fate and identity. However, trajectories of human cells remain largely unexplored due to the challenges of studying them with human samples. In this study, we investigate the proteome trajectory of iPSCs differentiation to hepatic stellate cells (diHSCs) and identify RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for diHSCs' commitment, identity, and activation.

MetALD: Clinical aspects, pathophysiology and treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) are the most prevalent causes of chronic liver disease worldwide. Both conditions have many pathophysiological mechanisms in common, such as altered lipid and bile acid metabolism, and share some similar clinical features. Furthermore, metabolic risk factors and alcohol often co-exist in the same individuals and have recently been shown to act synergistically to markedly increase the risk of liver disease.

Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis.

Background And Objectives: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options.

Alcoholic Foamy Degeneration, an Entity Resembling Alcohol-Associated Hepatitis: Diagnosis, Prognosis, and Molecular Profiling.

Background & Aims: Alcoholic foamy degeneration (AFD) is a condition with similar clinical presentation to alcohol-associated hepatitis (AH), but with a specific histologic pattern. Information regarding the prevalence and prognosis of AFD is scarce and there are no tools for a noninvasive diagnosis.

Methods: A cohort of patients admitted to the Hospital Clinic of Barcelona for clinical suspicion of AH who underwent liver biopsy was included.

Ductular reaction-associated neutrophils promote biliary epithelium proliferation in chronic liver disease.

Background & Aims: Ductular reaction expansion is associated with poor prognosis in patients with advanced liver disease. However, the mechanisms promoting biliary cell proliferation are largely unknown. Here, we identify neutrophils as drivers of biliary cell proliferation and the defective wound-healing response.

Hepatocyte dedifferentiation profiling in alcohol-related liver disease identifies CXCR4 as a driver of cell reprogramming.

Background & Aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood.

Hepatocyte Dedifferentiation Profiling In Alcohol-Related Liver Disease Identifies CXCR4 As A Driver Of Cell Reprogramming.

Background And Aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocytes markers and showing immature features. However, the mechanisms and the impact of hepatocyte dedifferentiation in liver disease are poorly understood.

The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.

Background And Aims: Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage.

Gene Variation at Immunomodulatory and Cell Adhesion Molecules Loci Impacts Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune disease triggered by a combination of environmental and host genetic factors, which results in the focal lymphocytic infiltration of exocrine glands causing eye and mouth dryness. Glandular infiltrates include T and B cell subsets positive for CD5 and/or CD6, two surface scavenger receptors involved in the fine-tuning of intracellular signals mediated by the antigen-specific receptor complex of T (TCR) and B (BCR) cells. Moreover, the epithelial cells of inflamed glands overexpress CD166/ALCAM, a CD6 ligand involved in homo and heterotypic cell adhesion interactions.

Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling.

Background And Aims: Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound-healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis.

Directed differentiation of human induced pluripotent stem cells to hepatic stellate cells.

Hepatic stellate cells (HSCs) are nonparenchymal liver cells responsible for extracellular matrix homeostasis and are the main cells involved in the development of liver fibrosis following injury. The lack of reliable sources of HSCs has hence limited the development of complex in vitro systems to model liver diseases and toxicity. Here we describe a protocol to differentiate human induced pluripotent stem cells (iPSCs) into hepatic stellate cells (iPSC-HSCs).

Programmed Death Ligand 1 Is Overexpressed in Liver Macrophages in Chronic Liver Diseases, and Its Blockade Improves the Antibacterial Activity Against Infections.

Background And Aims: Bacterial infections are common and severe in cirrhosis, but their pathogenesis is poorly understood. Dysfunction of liver macrophages may play a role, but information about their function in cirrhosis is limited. Our aims were to investigate the specific profile and function of liver macrophages in cirrhosis and their contribution to infections.

Ductular Reaction Cells Display an Inflammatory Profile and Recruit Neutrophils in Alcoholic Hepatitis.

Chronic liver diseases are characterized by the expansion of ductular reaction (DR) cells and the expression of liver progenitor cell (LPC) markers. In alcoholic hepatitis (AH), the degree of DR expansion correlates with disease progression and short-term survival. However, little is known about the biological properties of DR cells, their impact on the pathogenesis of human liver disease, and their contribution to tissue repair.