Search Results (1,173)

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is now recognized as the leading cause of chronic liver disease worldwide. MASLD spans a spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and is linked to progressive fibrosis and ultimately hepatocellular carcinoma (HCC). Growing evidence implicates cellular senescence (CS) and lipid droplets (LDs) as key drivers of disease progression, although their interaction remains poorly characterized. This review provides an integrative and stage-dependent synthesis of current mechanistic insights into how bidirectional crosstalk between CS and LD regulation shapes the transition from steatosis to MASH. Senescent hepatocytes display altered lipid metabolism, including upregulation of receptors such as cluster of differentiation (CD) 36, enhancing lipid uptake to meet increased energy demands. Initially, elevated free fatty acid influx can activate peroxisome-proliferator-activated receptor alpha (PPARα), promoting fatty acid oxidation (FAO) as a compensatory response. Over time, persistent CS under steatotic conditions leads to mitochondrial dysfunction and suppression of fatty acid oxidation (FAO), while the senescence-associated secretory phenotype (SASP), largely driven by nuclear factor—kappa B (NF-κB) signaling, promotes chronic hepatic inflammation. By framing LDs as active modulators of senescence-associated signaling rather than passive lipid stores, this review highlights how disruption of senescence–lipid feedback loops may represent a disease-modifying opportunity in MASLD progression. Full article

The fish liver, as the main detoxification organ, is highly susceptible to xenobiotic exposure, often resulting in various hepatopathies. The cytochrome P450 system plays a central role in xenobiotic metabolism, with cytochrome P450 reductase (CYPOR) supplying the electrons required for CYP enzyme activity. This study aimed to evaluate the relationship between the ecological state of a reservoir and fish health, including CYPOR levels, through hematological, bacteriological, and histological analyses. Samples of water and fish were collected from 12 littoral sites of Lake Ladoga. A total of 1360 specimens of fish from carp (Cyprinidae) and perch (Percidae) families were examined. For histological examination and CYPOR level determination, we selected 40 specimens using a blind randomization method. This sample size was sufficient for statistical analyses. Hematological smears were stained with azure eosin; bacteriological cultures were grown on multiple media; liver samples were stained with hematoxylin and eosin and Sudan III. CYPOR levels in liver homogenates were measured by ELISA-test. Physical and hydrochemical analyses indicated a high pollution level in the littoral zones. Isolated bacterial species were non-pathogenic but exhibited broad antibiotic resistance. Hematological evaluation revealed erythrocyte vacuolization and anisocytosis. Histological analysis showed marked fatty degeneration in hepatocytes, indicating toxic damage. CYPOR concentrations ranged from 0.3–0.4 ng/mL in healthy fish to 5–6 ng/mL in exposed specimens, showing strong correlation between environmental influence and enzyme activity. These findings demonstrate the potential of CYPOR as a sensitive biomarker for biomonitoring programs. The integrated methodological approach provides a model for assessing aquatic ecosystem health and identifying zones requiring priority remediation. Full article

Alcohol-associated liver disease (ALD) contributes substantially to the global burden of cirrhosis and liver-related mortality, driven by ethanol metabolism, oxidative stress, and dysregulated immune signaling. Despite rapidly growing evidence implicating interferon regulatory factors (IRFs) in ALD pathogenesis, an integrated framework linking ethanol-induced danger signals to cell-type-specific IRF programs is lacking. In this comprehensive review, we summarize current knowledge on IRF-centered signaling networks in ALD, spanning DAMP–PAMP sensing, post-translational IRF regulation, and downstream inflammatory, metabolic, and fibrogenic outcomes across various cell types in the liver, including hepatocytes and immune-related cells such as Kupffer cells, monocyte-derived macrophages, dendritic cells, T cells, hepatic stellate cells (HSC), and neutrophils. We also focus on how ethanol-driven DAMP and PAMP signals activate TLR4, TLR9, and cGAS–STING pathways to engage a coordinated network of IRFs—including IRF1, IRF3, IRF4, IRF5, IRF7, and IRF9—that collectively shape inflammatory, metabolic, and cell-fate programs across hepatic cell populations. We further highlight emerging therapeutic strategies such as STING/TBK1 inhibition, NETosis blockade, IL-22-based epithelial repair, and JAK-STAT modulation that converge on IRF pathways. In summary, this review outlines how IRFs contribute to ALD pathogenesis and discusses the potential implications for the development of targeted therapies. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a multifaceted systemic condition, with the mechanisms linking intrahepatic lesions to systemic complications remaining a significant enigma in the field. This review posits that extracellular vesicles (EVs) serve as pivotal mediators facilitating communication between the liver and the entire organism. Within the hepatic environment, lipotoxic hepatocyte-derived EVs modulate macrophage populations and stellate cells, thereby promoting inflammatory and fibrotic processes. Systemically, the liver engages in bidirectional communication with adipose tissue, the intestinal tract, the cardiovascular system, and the pancreas via EVs, thus orchestrating metabolic homeostasis. Furthermore, we critically evaluate non-invasive diagnostic strategies and emerging therapies, including both natural and engineered EVs, based on EV-based interventions. We highlight the substantial potential and current challenges associated with achieving precision medicine in MASLD through targeted modulation of this specific communication network. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a progressive spectrum of metabolic liver injury in which immune activation, metabolic stress, and stromal remodeling evolve in a tightly interdependent manner. Although early disease stages are dominated by metabolic overload, accumulating evidence indicates that immunometabolic rewiring and fibro-inflammatory amplification critically shape the transition toward metabolic dysfunction-associated steatohepatitis (MASH) and advanced fibrosis. This review synthesizes emerging insights into how hepatocyte stress responses, innate and adaptive immune circuits, and extracellular matrix-producing stromal populations interact to form a dynamic, feed-forward network driving disease progression. Particular emphasis is placed on the deterministic role of immune–fibrotic coupling in shaping clinical phenotypes, disease trajectory, and therapeutic responsiveness. Rather than focusing on individual molecular layers, we highlight how integrated clinical, imaging, and biomarker-informed frameworks can capture immune–fibrotic signatures relevant to risk stratification and precision intervention. Building on this systems-level perspective, we outline next-generation therapeutic strategies targeting immunometabolic circuits, cross-organ communication, and multi-system dysfunction. Finally, we discuss how future precision medicine—supported by integrative biomarker profiling and dynamic physiological assessment—may reshape MASLD management and improve long-term hepatic and cardiometabolic outcomes. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a continuum of hepatic pathological manifestations of the metabolic syndrome. Pathogenesis is not clearly understood despite recent progress, but Kupffer cells and bone marrow-derived macrophages (BMDMs) have a fundamental role. In this review, the multiple pathophysiological aspects of MASLD are presented, including genetics, insulin resistance, lipotoxicity, and inflammation. The participation of innate and adaptive immunity, as well as the implications of the recently described trained immunity, is presented. The interplay of the liver with the gut microbiota is also analyzed. A recent adipocentric theory and the various mechanisms of hepatocyte death are also described. The fundamental role of Kupffer cells and other liver macrophages is discussed in detail, including their extreme phenotypic plasticity in both the normal and the MASLD liver. The functional differentiation between pro-inflammatory and anti-inflammatory subpopulations and their protective or detrimental involvement is further described, including the participation of Kupffer cells and BMDMs in all aspects of MASLD pathogenesis. The role of macrophages in the development of advanced MASLD, including fibrosis and hepatocellular carcinoma, is analyzed and the lack of explanation for the transition from MASLD to MASH is recognized. Finally, current modalities of drug treatment are briefly presented and the effects of different drugs on macrophage polarization and functions are discussed. Full article

Background: Intestinal failure-associated liver disease (IFALD) is a serious complication in patients receiving parenteral nutrition, often exacerbated by inflammation, lipid overload, and oxidative stress. Nobiletin (NOB), a polymethoxylated flavone, is known for its anti-inflammatory and lipid-regulating properties. Methods: We employed an in vitro model using THLE-2 human hepatocytes and primary human cholangiocytes exposed to Intralipid (INT) and lipopolysaccharide (LPS) to simulate IFALD conditions. NOB was tested at non-toxic concentrations (10 and 25 µM) to assess its protective effects. MTT viability assays, multiplex bead-based immunoassays (MAGPIX), RT-qPCR, and Western blotting were used to evaluate changes in inflammation markers, gene expression, and protein signaling. Moreover, ALT and AST activities were used to assess hepatocellular injury. Results: NOB maintained high cell viability in THLE-2 hepatocytes and cholangiocytes, confirming its low cytotoxicity. NOB normalized ALT and AST activities in both tested cell lines, but the effect reached statistical significance only for ALT in cholangiocytes. Under IFALD-like conditions (LPS+INT), NOB significantly preserved metabolic activity in both cell types. In THLE-2 and cholangiocytes, NOB markedly reduced the phosphorylation of pro-inflammatory proteins JNK, NF-κB, and STAT3, indicating a broad inhibition of inflammatory signaling. Moreover, in THLE-2 cells, NOB upregulated lipid metabolism-related genes (PRKAA2, CYP7A1, and ABCA1) and decreased oxidative stress, thereby enhancing the nuclear translocation of Nrf2 and increasing SOD1 level, which supports the activation of antioxidant defenses. Conclusions: NOB exhibits hepatoprotective properties under IFALD-like conditions in vitro, likely through modulation of inflammation-related signaling and lipid metabolism pathways. Full article

Bupleuri radix has demonstrated therapeutic potential in treating liver disorders, and polysaccharides are one of its main bioactive components; however, the effects of Bupleuri radix polysaccharides (BRP) on metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. This study aimed to identify the BRP fractions with anti-MASLD activity and elucidate their underlying mechanisms. We prepared BRP and characterized its physicochemical properties. It markedly alleviated liver injury and restored intestinal barrier function in MASLD. The correlation analysis between transcriptomics and targeted metabolomics showed that BRP restored intestinal acetic acid and propionic acid, with acetic acid activating AMPK and propionic acid promoting cholesterol efflux and metabolism in the liver, thereby reducing lipid accumulation in hepatocytes. Mechanistically, 16S RNA sequencing and diversity analysis indicated that BRP enriched short chain fatty acids (SCFAs)-producing bacteria, such as the genus Muribaculaceae, and inhibited pro-inflammatory microbiota. Interestingly, Paramuribaculum intestinale (P. intestinale), a representative species in the genus Muribaculaceae, synergistically enhanced BRP in improving liver and colonic mucosal damage in MASLD. In conclusion, our findings revealed that BRP improved MASLD by regulating Muribaculaceae-derived SCFAs in the gut–liver axis and could be used in combination with probiotics as a novel therapeutic strategy for MASLD. Full article

The liver is the central organ in metabolism; however, modeling hepatic diseases remains limited by current experimental models. Animal models frequently fail to predict human liver physiology, while primary hepatocytes rapidly dedifferentiate in culture. We performed comprehensive transcriptomic profiling of induced pluripotent stem cells (iPSCs) differentiation into hepatocyte-like cells (HLCs) under two-dimensional (2D) and three-dimensional (3D) culture conditions. RNA sequencing analysis revealed the sequential activation of lineage-specific markers across major developmental stages: definitive endoderm (FOXA2, SOX17, CXCR4, CER1, GATA4), posterior foregut (PROX1, GATA6), and hepatoblasts (HNF4A, AFP). Comparative analysis demonstrated a markedly enhanced hepatic gene expression of 3D organoids, as demonstrated by a 33-fold increase in HNF4A expression and elevated levels of mature hepatocyte markers, including ALB, SERPINA1, and UGT2B15. However, the 3D cultures retained fetal characteristics (290-fold higher AFP expression) and exhibited significantly impaired metabolic function, with CYP3A4 expression levels reduced by 2000-fold compared to the adult human liver. This partial maturation was further supported by a moderate correlation with adult liver tissue (ρ = 0.57). We demonstrated high reproducibility across five biologically distinct iPSCs lines, including those derived from patients with rare monogenic disorders. The establishment of quantitative benchmarks provides a crucial tool for standardizing in vitro liver models. Furthermore, we delineate the specific limitations of the current model, highlighting the need for further protocol optimization to enhance metabolic maturation and P450 enzyme activity. Functional validation of metabolic activity (CYP enzyme assays, albumin secretion) was not performed; therefore, conclusions regarding hepatocyte functionality are based on transcriptomic evidence. Full article

Abnormal lipid metabolism is a key feature of many diseases. Therefore, investigating its underlying mechanisms is of great importance. Recently, blue light has shown promise as a drug-free way to influence energy metabolism, relying on the light-sensitive protein Opsin 3 (Opn3). This study aimed to investigate the effects of blue light irradiation on lipid droplet degradation in cells and its molecular mechanism, while also evaluating its potential antiviral effects. The results demonstrate that exposure to 470–480 nm blue light significantly reduced oleic-acid-induced intracellular lipid droplet accumulation and decreased triglyceride and total cholesterol levels, an effect dependent on the Opn3. It was found that blue light affects the Pparα signaling pathway through Opn3, and, at the same time, blue light and Opn3 promote autophagy mediated by p62 protein, thereby cooperatively regulating lipid droplet degradation. In Opn3 knockout cells, blue-light-induced lipid droplet degradation, nuclear accumulation of Pparα, and autophagic effects were all suppressed. Additionally, the study unexpectedly observed that blue light, via Opn3, significantly suppressed the replication of VSV, H1N1 and EMCV and alleviated virus-induced cell death and inflammatory responses. This study reveals the critical role of the blue light–Opn3-Pparα/p62 axis in regulating lipid droplet degradation in hepatocytes and identifies a novel antiviral function of Opn3-mediated blue light exposure. These findings provide a new theoretical basis and potential targets for innovative therapeutic strategies against metabolic diseases and viral infections. Full article

Acute liver injury (ALI) is a potentially life-threatening condition lacking effective clinical drugs. Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of both inflammation and metabolism. In ALI, HIF-1α expressions are upregulated, but the role of HIF-1α in hepatocytes and whether it can be targeted remain unclear. Herein, clinical samples and ALI murine models including lipopolysaccharide/D-galactosamine (LPS/D-GalN), acetaminophen (APAP), and thioacetamide (TAA) revealed an increase in HIF-1α expression and ferroptosis. Using HIF-1α gain and loss of function mouse and hepatocyte culture models, we demonstrated that HIF-1α upregulation exacerbated liver ferroptosis and injury. Mechanistically, HIF-1α/transferrin receptor protein 1 (TFR1) axis drives hepatic iron overload, promoting ferroptotic cell death and liver injury. In addition, TFR1 inhibition reversed HIF-1α-induced ALI. Importantly, pharmacological inhibition of HIF-1α and TFR1 significantly reduced ferroptosis and mitigated liver injury both in vivo and in vitro. Together, our findings demonstrate the pathological role of hepatic HIF-1α, which may serve as a promising target of therapeutic intervention. Full article

The insulin-like growth factor (IGF) axis orchestrates hepatic development, regeneration, and metabolism, yet the roles of individual IGF-binding proteins (IGFBPs) remain incompletely defined. IGFBP-6, a high-affinity, IGF-II-preferring binding protein, has emerged as a context-dependent modulator of IGF bioavailability and cell signaling with additional IGF-independent actions. This review synthesizes current evidence on IGFBP-6 in liver biology and disease. We first outline hepatic expression, regulation, and post-translational processing of IGFBP-6 across development, homeostasis, and injury, and summarize its effects on canonical IGF-II/IGF1R signaling and downstream phosphatidylinositol 3-kinase—protein kinase B (PI3K–AKT) and rat sarcoma—mitogen-activated protein kinase (RAS–MAPK) pathways. We then evaluate experimental and clinical data linking IGFBP-6 to steatotic liver disease, inflammation, and fibrogenesis, including putative roles in hepatocyte stress responses, stellate cell activation, and extracellular matrix remodeling. Finally, we examine IGFBP-6 in primary liver cancers—hepatocellular carcinoma and cholangiocarcinoma—highlighting evidence for tumor-suppressive versus pro-migratory activities, potential crosstalk with hypoxia, Wnt/β-catenin and TGF-β signaling, and interactions with the tumor immune microenvironment. Across conditions, we assess the translational potential of IGFBP-6 as a circulating or tissue biomarker, its utility for patient stratification, and prospects for therapeutic targeting—either by modulating IGF-II sequestration or exploiting IGF-independent mechanisms. We conclude by identifying key knowledge gaps, methodological limitations, and priorities for future studies, including standardized measurement, cell-type-resolved profiling, and in vivo perturbation in clinically relevant models. Collectively, the review positions IGFBP-6 as a nuanced regulator of liver pathophysiology and a promising, yet underexplored, lever for diagnosis and therapy. Full article

Obesity plays a crucial role in the progression of insulin resistance and type 2 diabetes which are related to inflammation and liver disease. GATA-3 is a transcription factor that is involved in adipogenesis and inflammation. Therefore, it could be a potential therapeutic target for obesity-associated metabolic disorders. This study aimed to examine the effects of GATA-3 suppression on body weight, fat depot redistribution, liver histopathology, and inflammatory markers in transgenic db/db obese mice. Male db/db mice received subcutaneous injections of GATA-3-specific DNAzyme (hgd40; 10 or 100 µg/mL), pioglitazone (as a positive control), or vehicle only (as a negative control), twice weekly for two weeks. Body weight, organ weights, liver histopathology, mRNA expression of selected genes and serum cytokine levels were assessed. GATA-3 expression was not region specific, and its suppression did not significantly affect fat depot distribution or organ weights. However, the low dose of hgd40 accelerated body weight gain transiently. It also increased Il10 mRNA expression in the liver and significantly increased IL-10 protein concentration in the serum. In addition, a high dose of hgd40 resulted in a marked decrease in hepatocyte ballooning degeneration. These findings suggest that GATA-3 suppression may modulate inflammation and liver injury in obesity, warranting further investigation into its therapeutic potential for obesity-related metabolic disorders. Full article

Hepatocyte nuclear factor 4 α (HNF4α) is a master transcriptional regulator essential for the maintenance of epithelial cell identity and function. Beyond its well-established role in controlling metabolic and differentiation programs, recent evidence highlights HNF4α as a key determinant of epithelial epigenetic reprogramming. Through direct interaction with chromatin modifiers and pioneer factors, HNF4α contributes to the establishment, maintenance, and dynamically reshaping of epithelial-specific transcriptional programs at epigenetic level. In this review, we summarize current knowledge on how HNF4α shapes chromatin organization by recruiting chromatin modifiers, modulating nucleosome positioning and regulating chromatin loop formation, thus directing tissue-specific gene expression. We also examine its direct regulation of epigenetic modifiers, as well as of epi-miRNAs and epi-lncRNAs, underscoring its role in coordinating chromatin remodeling with transcriptional networks. Finally, we address how dynamic HNF4α occupancy and activity influence context-dependent transcriptional outputs, and how disease-related alterations of its expression and function can contribute to epithelial dysfunction. Understanding the epigenetic functions of HNF4α provides new insights into epithelial biology and reveals potential therapeutic opportunities for restoring epithelial homeostasis in disease contexts. Full article

Compound yeast culture (CYC) is known to enhance animal health, but its effects on hepatic immune function are unclear. This study systematically examined CYC’s regulatory effects on the liver of weaned lambs using transcriptomics and integrative bioinformatics. Ten lambs were randomly assigned to a control diet or a basal diet supplemented with 30 g/d per head of Saccharomyces cerevisiae and Kluyveromyces marxianus co-culture (CYC group) for 42 days. Histological analysis showed that CYC improved hepatocyte arrangement and sinusoidal integrity, suggesting enhanced hepatic tissue stability. Cytokine analysis revealed CYC significantly increased IL-6 and IL-1β while reducing IL-10, TGF-β1, TNF-α, and CXCL9, indicating a bidirectional modulation of the immune response. Additionally, CYC enhanced antioxidant defenses by increasing T-SOD, GSH-Px, and T-AOC activities and decreasing MDA content. Transcriptomic sequencing indicated that CYC reshaped hepatic gene expression. Upregulated genes were enriched in immune-regulatory and structural pathways, including PI3K-AKT signaling, ECM–receptor interactions, Toll-like receptor pathways, and cell adhesion molecules. Protein-level validation further confirmed activation of PI3K and AKTAKT phosphorylation with limited engagement of NF-κB signaling. Conversely, downregulated genes were mainly associated with oxidative stress and energy metabolism, such as ROS-related pathways and MAPK signaling. WGCNA identified key hub genes (PTPRC, CD86, and ITGAV), which correlate with pro-inflammatory factors and participate in immune recognition, T-cell activation, and cell adhesion. These data suggest that CYC promotes hepatic immune homeostasis by enhancing immune signaling, stabilizing tissue architecture, and modulating oxidative stress/metabolic processes. This study provides mechanistic insights into CYC’s regulation of liver immune function and supports its targeted application as a functional feed additive for ruminants. Full article