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Persistent activation of hepatic stellate cells (HSCs) in the injured liver leads to the progression of liver injury from fibrosis to detrimental cirrhosis. In a previous study, we have shown that survivin protein is upregulated during the early activation of HSCs, which triggers the onset of liver fibrosis. However, the therapeutic potential of targeting survivin in a fully established fibrotic liver needs to be investigated. In this study, we chemically induced hepatic fibrosis in mice using carbon tetrachloride (CCl4) for 6 weeks, which was followed by treatment with a survivin suppressant (YM155). We also evaluated survivin expression in fibrotic human liver tissues, primary HSCs, and HSC cell line by histological analysis. αSMA+ HSCs in human and mice fibrotic liver tissues showed enhanced survivin expression, whereas the hepatocytes and quiescent (qHSCs) displayed minimal expression. Alternatively, activated M2 macrophage subtype induced survivin expression in HSCs through the TGF-β-TGF-β receptor-I/II signaling. Inhibition of survivin in HSCs promoted cell cycle arrest and senescence, which eventually suppressed their activation. In vivo, YM155 treatment increased the expression of cell senescence makers in HSCs around fibrotic septa such as p53, p21, and β-galactosidase. YM155 treatment in vivo also reduced the hepatic macrophage population and inflammatory cytokine expression in the liver. In conclusion, downregulation of survivin in the fibrotic liver decreases HSC activation by inducing cellular senescence and modulating macrophage cytokine expression that collectively ameliorates liver fibrosis.

Liver fibrosis of different etiologies is a serious health problem worldwide. There is no effective therapy available for liver fibrosis except the removal of the underlying cause of injury or liver transplantation. Development of liver fibrosis is caused by fibrogenic myofibroblasts that are not present in the normal liver, but rather activate from liver resident mesenchymal cells in response to chronic toxic or cholestatic injury. Many studies indicate that liver fibrosis is reversible when the causative agent is removed. Regression of liver fibrosis is associated with the disappearance of activated myofibroblasts and resorption of the fibrous scar. In this review, we discuss the results of genetic tracing and cell fate mapping of hepatic stellate cells and portal fibroblasts, their specific characteristics, and potential phenotypes. We summarize research progress in the understanding of the molecular mechanisms underlying the development and reversibility of liver fibrosis, including activation, apoptosis, and inactivation of myofibroblasts.

Non-alcoholic fatty liver disease (NAFLD), a major cause of chronic liver disease, is known to affect a quarter of the global adults. Natural history of NAFLD shows interindividual variation, traditionally it progresses from simple steatosis to steatohepatitis to fibrosis/cirrhosis and finally yet rarely to hepatocellular carcinoma. It is largely a lifestyle-related disease and is often labeled as the hepatic manifestation of metabolic syndrome. Both prevention and control of NAFLD include controlling risk factors (obesity, diabetes mellitus, hypertension and dyslipidemia), through lifestyle modification and medications. Drug therapy for NAFLD per se is still evolving and till date, no drugs are approved. It is clinically silent, especially in the early stages, and is a diagnosis of exclusion. Certain easily calculated indices can stratify cases into high or low risk for advanced fibrosis, thereby dictating appropriate monitoring and treatment measures. In addition to complications specific to liver disease in those who do progress to advanced fibrosis or cirrhosis, an increased risk of nonliver disease-related morbidity and mortality is also present. Challenges are manifold and include rising burden due to ever-growing epidemic of diabetes and obesity, low public awareness, fragmented healthcare, no approved drugs, and dearth of data on magnitude and epidemiology of the disease. The recent integration of NAFLD into the National Program for Prevention and Control of Non-Communicable Diseases (NPCDCS) by the Ministry of Health and Family Welfare of India is a welcome step in this direction as the contributory factors are mostly the same for all diseases and controlling any one or all of them will have a desired impact on the prevalence of all the diseases under this program. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Liver cirrhosis is a significant global health concern, and cirrhotic cardiomyopathy (CCM) is a notable complication affecting both adults and children. While CCM is well-studied in adults, understanding its manifestation and diagnostic criteria in pediatric patients remains a challenge. This review explores the evidence for structural and functional cardiac alterations in children with liver cirrhosis. Structural abnormalities, including increased left ventricular mass index (LVMI) and altered left ventricular wall thickness ratios, are prevalent in pediatric CCM. These abnormalities persist even after liver transplantation, highlighting the systemic impact of liver disease. Evidence suggests that altered systolic and diastolic function, as well as electrocardiographic abnormalities such as prolonged QT intervals, are common in pediatric CCM. Blood biomarkers, including brain natriuretic peptide (BNP) and troponin levels, offer insights into cardiac function in pediatric cirrhotic patients. Elevated BNP levels correlate with adverse outcomes, indicating its potential as a prognostic marker. However, further research is needed to elucidate the diagnostic utility of these biomarkers in pediatric CCM. Conclusion: This review provides estimates of the standardized mean difference among selected cardiac parameters in children with and without cirrhosis. Tailored diagnostic criteria and comprehensive assessment methods will be essential for accurate diagnosis and effective management of pediatric CCM. What is Known: • CCM adds to the burden of care of patients with cirrhosis. • Diagnostic criteria for adults are evolving, but there are no specific criteria for pediatric CCM. What is New: • Cardiac function in children with cirrhosis indicates some parameters not considered in adults are altered. • Effect size estimations for certain parameters provide a guideline for future research into pediatric CCM. [ABSTRACT FROM AUTHOR]

Globally, nearly 2 million deaths annually are attributed to the development of liver diseases, with liver cancer and cirrhosis being particularly prominent, which makes liver disease a significant global health concern. Cirrhosis is closely linked to the evolution of hepatitis, hepatic fibrosis and fatty liver. However, most liver diseases have an insidious onset, are challenging to treat and the prognosis and efficacy of current therapies are unsatisfactory, which can result in irreversible functional damage to the liver. Therefore, there is an urgent need to explore the molecular mechanisms underlying liver disease and identify new biomarkers and therapeutic targets. In previous years, microRNAs (miRs), a class of short non-coding RNAs comprising 17-25 nucleotides, have attracted attention for their roles in various types of liver diseases. Among them, miR-22 serves a unique role in mediating multiple pathway mechanisms and epigenetic modifications and can act both as an inhibitor of liver cancer and a metabolic blocker. Given its close association with the liver, several studies have reported that the differential expression of miR-22 regulates the metabolic process of liver cancer and is involved in the evolution of hepatic fibrosis and steatohepatitis, making it a potential target for early diagnosis and treatment. The present manuscript aimed to comprehensively review the key role of miR-22 in the evolution of liver diseases and offer valuable references and guidance for subsequent studies by identifying its specific mechanism of action and future development prospects. [ABSTRACT FROM AUTHOR]

Longitudinal analysis of antibody responses following three-dose COVID-19 vaccination in patients with chronic liver disease (CLD) has been limited. From August 2021 to February 2023, sequential anti -SARS-CoV-2 spike IgG titers were determined in 45 patients with CLD who received two or three doses of COVID-19 vaccine. The geometric mean of anti-spike IgG at four weeks after the second and third doses were 1313.16 BAU/mL and 3042.29 BAU/mL, respectively, and it decreased significantly from four to 24 weeks after the second (1313.16 vs. 198.42 BAU/mL, p = 0.002) and the third (3042.29 vs. 636.71 BAU/mL, p < 0.001) dose. The anti-spike IgG titers in participants receiving prime-boost homologous mRNA vaccines (BNT162b2 or mRNA-1273) were comparable between participants with and those without significant liver fibrosis at each follow-up time point. This study demonstrated a notable decrease in anti-spike IgG after completion of the vaccination schedule in patients with CLD, highlighting the importance of additional booster doses. [ABSTRACT FROM AUTHOR]

This study explored the mechanism of microRNA (miR)-30a in the activation of hepatic stellate cells (HSCs) to deepen the understanding of the pathogenesis of liver fibrosis. Subsequent to knockdown and ectopic experiments, HSCs were induced with 10 ng/mL transforming growth factor (TGF)-β1 to inspect the role of the miR-30a/TGF-β receptor 1 (TGFBR1) axis in HSC proliferation and activation. qRT-PCR was utilized to examine TGFBR1 mRNA and miR-30a expression and western blot to test TGFBR1, alpha smooth muscle actin (α-SMA), Collagen I and mothers against DPP homolog 2/3 (Smad2/3) protein expression. The fluorescence intensity of α-SMA was measured with immunofluorescence staining. The interaction of TGFBR1 with miR-30a was tested with a dual-luciferase reporter assay. TGF-β1 treated HSCs had upregulated expressions of α-SMA and Collagen I. In addition, downregulated miR-30a, upregulated TGFBR1 and activated TGF-β1/Smad2/3 pathway were found in activated HSCs. Upregulation of miR-30a or downregulation of TGFBR1 suppressed the activation and growth of HSCs. miR-30a repression activated the TGF-β1/Smad2/3 pathway and promoted HSC proliferation and activation, while suppression of TGFBR1 revered these effects. miR-30a was an upstream regulatory factor of TGFBR1. miR-30a blocks the TGF-β1/Smad2/3 pathway to inhibit HSC activation against liver fibrosis by targeting TGFBR1. [ABSTRACT FROM AUTHOR]

To explore the value of ultrasound elastography combined with serological indicators in the diagnosis of liver fibrosis in chronic hepatitis B. A total of 156 patients with chronic hepatitis B from April 2020 to February 2022 were enrolled in this study as subjects. They were assigned to the liver fibrosis group (n=115) and the non-liver fibrosis group (n=41) according to whether the patients had liver fibrosis. They were divided into S1 stage (n=48), S2 stage (n=38), and S3 stage (n=29) according to histopathological staging criteria. Shear wave elastography (SWE) values, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), procollagen type III (PCIII), and laminin (LN) were compared among patients in each stage. Spearman's method was utilized to analyze the correlation of liver serum biochemical indicators and SWE value with liver fibrosis. The predictive performance of SWE value and serological indicators was analyzed using receiver operating characteristic curves. According to Spearman's method, the liver fibrosis stage was positively correlated with SWE value. Serological indicators combined with ultrasound elastography can accurately assess the degree of liver fibrosis in patients with chronic hepatitis B and provide a basis for clinical judgment. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL–EASD–EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as the fibrosis-4 index [FIB-4]) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification—including weight loss, dietary changes, physical exercise and discouraging alcohol consumption—as well as optimal management of comorbidities—including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for type 2 diabetes or obesity, if indicated—is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis. [ABSTRACT FROM AUTHOR]

Liver diseases emerge as a serious threat to humans worldwide due to increasing morbidity and mortality. Liver disease related deaths accounts for one third of all disease related death globally. A simple fatty liver if unattended advances further to liver fibrosis, cirrhosis and hepatocellular carcinoma. During liver fibrogenesis, hepatic stellate cells gets activated into myofibroblast like cells and exhibit proliferative and fibrogenic features. Targeting these activated hepatic stellate cells offer promising therapeutic approach towards liver fibrosis management. To date there is no Food and Drug Administration approved treatments for liver fibrosis. However, a large number of clinical trials are being conducted employing monoclonal antibodies, drugs, dietary supplements and herbal medicines. A vast number of research findings demonstrated nutraceuticals to be effective against experimental liver fibrosis both in vitro and in vivo. Nutraceuticals typically regulate key signaling pathways in activated hepatic stellate cells and exhibit anti-fibrotic effect. In this review, the mechanistic action of nutraceuticals targeting activated hepatic stellate cells were summarized to establish them as a possible therapeutic candidate for liver fibrosis. [ABSTRACT FROM AUTHOR]

Zinc plays a pivotal role in tissue regeneration and maintenance being as a central cofactor in a plethora of enzymatic activities. Hypozincemia is commonly seen with chronic liver disease and is associated with an increased risk of liver fibrosis development and hepatocellular carcinoma. Previously favorable effects of zinc supplementation on liver fibrosis have been shown. However, the underlying mechanism of this effect is not elucidated. Liver fibrosis was induced in mice by using CCl4 injection, followed by treatment with zinc chloride (ZnCl2) both at fibrotic and sham groups, and their hepatocytes were isolated. Our results showed that the administration of ZnCl2 restored the depleted cytosolic zinc levels in the hepatocytes isolated from the fibrotic group. Also, alpha-smooth muscle actin (αSMA) expression in hepatocytes was decreased, indicating a reversal of the fibrotic process. Notably, ZIP14 expression significantly increased in the fibrotic group following ZnCl2 treatment, whereas in the sham group ZIP14 expression decreased. Chromatin immunoprecipitation (ChIP) experiments revealed an increased binding percentage of Metal-regulatory transcription factor 1 (MTF1) on ZIP14 promoter in the hepatocytes isolated from fibrotic mice compared to the sham group after ZnCl2 administration. In the same group, the binding percentage of the histone deacetylase HDAC4 on ZIP14 promoter decreased. Our results suggest that the ZnCl2 treatment ameliorates liver fibrosis by elevating intracellular zinc levels through MTF1-mediated regulation of ZIP14 expression and the reduction of ZIP14 deacetylation via HDAC4. The restoration of intracellular zinc concentrations and the modulation of ZIP14 expression by zinc orchestrated through MTF1 and HDAC4, appear to be essential determinants of the therapeutic response in hepatic fibrosis. These findings pave the way for potential novel interventions targeting zinc-related pathways for the treatment of liver fibrosis and associated conditions. [ABSTRACT FROM AUTHOR]

Liver fibrosis, arising from factors such as viral infections or metabolic disorders, represents an ongoing global health challenge and is a major risk factor for hepatocellular carcinoma. Unfortunately, there are no clinically approved drugs available for its treatment. Recent studies have illuminated the pivotal role of macrophage recruitment in the pathogenesis of liver fibrosis, presenting a potential therapeutic target. Therefore, it holds great promise to develop novel anti‐fibrotic therapies capable of inhibiting this process. Herein, a drug‐loaded biomimetic nanodecoy (CNV‐C) is developed by harnessing genetically engineered cellular vesicles for the treatment of liver fibrosis. CNV‐C is equipped with a C‐C motif chemokine receptor 2 (CCR2)‐overexpressed surface, enabling it to selectively neutralize elevated levels of C‐C motif chemokine ligand 2 (CCL2), thereby reducing macrophage infiltration and the subsequent production of the fibrogenic cytokine transforming growth factor β (TGF‐β). Moreover, curcumin, an anti‐fibrotic agent, is loaded into CNV‐C and delivered to the liver, facilitating its efficacy in suppressing the activation of hepatic stellate cells by blocking the downstream TGF‐β/Smad signaling. This combinational therapy ultimately culminates in the alleviation of liver fibrosis in a mouse model induced by carbon tetrachloride. Collectively, the findings provide groundbreaking proof‐of‐concept for employing genetically modified nanodecoys to manage liver fibrosis, which may usher in a new era of anti‐fibrotic treatments. [ABSTRACT FROM AUTHOR]

Background: Liver fibrosis is a common pathological process of chronic liver disease, characterized by excessive deposition of extracellular matrix (ECM). Mesenchymal stem cells (MSCs) have been found to have potential therapy effect on liver fibrosis, but the mechanism involved was still unclear. The objective of this study is to investigate the therapeutic efficacy of adipose-derived mesenchymal stem cells (ADMSCs) on the treatment of liver fibrosis, with particular emphasis on elucidating the underlying mechanism of action through which ADMSCs inhibit the activation of hepatic stellate cells (HSCs). Methods: ADMSCs were isolated from adipose tissue and injected intravenously into hepatic fibrosis model of rats. The histopathological changes, liver function, collagen deposition, the expression of fibroin and Hippo pathway were evaluated. In vitro, ADMSCs were co-cultured with HSCs activated by transforming growth factor beta 1 (TGF-β1), and the inhibitor of Hippo pathway was used to evaluate the therapeutic mechanism of ADMSCs transplantation. Results: The results showed that after the transplantation of ADMSCs, the liver function of rats was improved, the degree of liver fibrosis and collagen deposition were reduced, and the Hippo signaling pathway was activated. In vitro, ADMSCs can effectively inhibit the proliferation and activation of HSCs induced by TGF-β1 treatment. However, the inhibitory effect of ADMSCs was weakened after blocking the Hippo signaling pathway. Conclusions: ADMSCs inhibit HSCs activation by regulating YAP/TAZ, thereby promoting functional recovery after liver fibrosis. These findings lay a foundation for further investigation into the precise mechanism by which ADMSCs alleviate liver fibrosis. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods and Results Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a heterogenous clinical and histopathological entity, where multiple metabolic co‐factors are intertwined with high interindividual variability. The impact and severity of each factor (including obesity and type 2 diabetes) define a systemic dysmetabolism that can lead to either advanced liver disease and its complication (including hepatocellular carcinoma and clinical events related to portal hypertension) or extrahepatic events: incident cardiovascular disease, chronic kidney disease and extrahepatic cancers. The balance between environmental factors and genetic susceptibility has unique implications in MASLD: the intermittent injury of metabolic co‐factors, their fluctuation over time and their specific management, are counterbalanced by the presence of gene variants that can significantly impact the disease at multiple levels. The I148M variant in the PNPLA3 gene is the most investigated genetic susceptibility that induces a more severe steatohepatitis, enhanced fibrogenesis and can shape the incidence of long‐term clinical events regardless of, or worsened by, other metabolic risk factors.In this review, we will summarise the updated evidence on the natural history of MASLD accounting for classical metabolic risk factors, the role of PNPLA3 in clinical sub‐phenotyping (e.g., ‘lean MASLD’), impact on disease severity and fibrosis progression, as well as its role for prognostication, alone or in combination with non‐invasive tools into polygenic risk scores. [ABSTRACT FROM AUTHOR]

Although single treatment with sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction‐associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 groups. All animals, except the NC group, received high‐fructose/high‐fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high‐fructose/high‐fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non‐alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP‐1/PPARγ), oxidative stress (MDA/H2O2), inflammation (IL1β/IL6/TNF‐α), fibrosis (TGF‐β1/α‐SMA), and apoptosis (TUNEL/Caspase‐3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin‐dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti‐inflammatory (IL‐10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose‐transporting and lipid‐regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co‐therapy against diabetes‐induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti‐inflammatory, anti‐oxidative, and anti‐fibrotic pathways. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Methods Results Conclusions Since its discovery, the patatin‐like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified.We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation‐induced fibrosis.Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo‐apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP‐1, LXRα and TGFβ activity and signalling.The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations. [ABSTRACT FROM AUTHOR]

An in silico target discovery pipeline was developed by including a directional and weighted molecular disease network for metabolic dysfunction-associated steatohepatitis (MASH)-induced liver fibrosis. This approach integrates text mining, network biology, and artificial intelligence/machine learning with clinical transcriptome data for optimal translational power. At the mechanistic level, the critical components influencing disease progression were identified from the disease network using in silico knockouts. The top-ranked genes were then subjected to a target efficacy analysis, following which the top-5 candidate targets were validated in vitro. Three targets, including EP300, were confirmed for their roles in liver fibrosis. EP300 gene-silencing was found to significantly reduce collagen by 37%; compound intervention studies performed in human primary hepatic stellate cells and the hepatic stellate cell line LX-2 showed significant inhibition of collagen to the extent of 81% compared to the TGFß-stimulated control (1 µM inobrodib in LX-2 cells). The validated in silico pipeline presents a unique approach for the identification of human-disease-mechanism-relevant drug targets. The directionality of the network ensures adherence to physiologically relevant signaling cascades, while the inclusion of clinical data boosts its translational power and ensures identification of the most relevant disease pathways. In silico knockouts thus provide crucial molecular insights for successful target identification. [ABSTRACT FROM AUTHOR]

Liver fibrosis, a chronic and long-term disease, can develop into hepatocellular carcinoma (HCC) and ultimately lead to liver failure. Early diagnosis and effective treatment still face significant challenges. Liver inflammation leads to liver fibrosis through continuous activation of hepatic stellate cells (HSCs) and the accumulation of immune cells. Intracellular communication among various immune cells is important for mediating the inflammatory response during fibrogenesis. Extracellular vesicles (EVs), which are lipid bilayer membrane-enclosed particles naturally secreted by cells, make great contributions to cell-cell communication and the transport of bioactive molecules. Nearly all the cells that participate in liver fibrosis release EVs loaded with lipids, proteins, and nucleic acids. EVs from hepatocytes, immune cells and stem cells are involved in mediating the inflammatory microenvironment of liver fibrosis. Recently, an increasing number of extracellular vesicle-based clinical applications have emerged, providing promising cell-free diagnostic and therapeutic tools for liver fibrosis because of their crucial role in immunomodulation during pathogenesis. The advantages of extracellular vesicle-based therapies include stability, biocompatibility, low cytotoxicity, and minimal immunogenicity, which highlight their great potential for drug delivery and specific treatments for liver fibrosis. In this review, we summarize the complex biological functions of EVs in the inflammatory response in the pathogenesis of liver fibrosis and evaluate the potential of EVs in the diagnosis and treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

AbstractThis study proposes a novel model employing nonlinear ordinary differential equations to dissect HCV dynamics. Six distinct population groups are delineated: Susceptible, Treatment, Responder, Non-Responder, Cured, and Fibrosis. A detailed numerical analysis of this model was conducted, tracking the predicted trends over a span of 20 years. The primary objective of this analysis is to assess and confirm the model’s predictive accuracy and its potential to supplant invasive diagnostic methods in monitoring the progression of liver fibrosis. By incorporating various control parameters, namely u1(t),u2(t), and u3(t), the model offers a nuanced perspective on disease progression and treatment outcomes. Parameter u1(t) modulates treatment-induced fibrosis progression, providing a crucial lever for mitigating treatment-related side effects. u2(t) reflects treatment effectiveness, capturing the proportion of responders within the treatment cohort. Meanwhile, u3(t) governs fibrosis progression in non-responders, shedding light on the disease’s natural trajectory without effective treatment. [ABSTRACT FROM AUTHOR]

The purpose of this study was to explore the correlation between Hashimoto's thyroiditis and Metabolic dysfunction-associated fatty liver disease (MAFLD), and at the same time to screen high-risk groups for liver fibrosis in MAFLD, find out the high-risk related indicators. The physical examination population was included as the study subjects and was grouped according to the diagnostic criteria for MAFLD. APRI > 1 or NFS > 0.676 or FIB-4 > 2.67were used to assess people at high risk of liver fibrosis, and logistic regression analysis was used to identify risk factors associated with high risk of liver fibrosis in MAFLD. ROC curves are used to look for indicators of diagnostic value. The proportion of people with Hashimoto's thyroiditis was lower in the MAFLD group. The MAFLD high-risk group for liver fibrosis had higher TSH levels, lower FT3 and FT4 levels, higher TGAB levels, and differences in biochemical markers. Age, BMI, FBG, and AST are risk factors for the high risk of liver fibrosis in MAFLD patients. ROC curve analysis showed that the AUC of age was 0.741 (0.721–0.761), and the optimal stage value was 57.5 years, while the AUC of AST was 0.729 (0.707–0.751), and the optimal cut-off value was 39.5 U/L. Age, BMI, FBG, and AST are risk factors for the high risk of liver fibrosis in MAFLD patients.The age is greater than or equal to 57.5 years, or the AST is greater than or equal to 39.5 U/L, indicating that the MAFLD patients are at high risk of liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: The impact of liver fibrosis on the clinical outcomes of patients with sepsis-induced coagulopathy (SIC) is not well understood. This study aimed to evaluate the association between liver fibrosis scores and in-hospital mortality in SIC patients. Methods: In this retrospective observational cohort study, data were collected from patients diagnosed with sepsis and admitted to the ICU at the First Affiliated Hospital of Wenzhou Medical University between January 2017 and December 2023. Liver fibrosis was evaluated using three scores: Fibrosis-4 (Fib-4), Aspartate Aminotransferase–to–Platelet Ratio Index (APRI), and Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS). Patients were divided into tertiles according to their liver fibrosis scores, and the primary outcome was in-hospital mortality. Multivariable logistic regression and restricted cubic spline regression analyses were used to assess associations, complemented by sensitivity analyses through subgroup evaluations. Results: The cohort included 948 patients diagnosed with SIC with an in-hospital mortality of 26.16%. Multivariate logistic regression analysis revealed a significant association between higher liver fibrosis scores and increased in-hospital mortality. Specifically, patients in the highest tertile of Fib-4, APRI, and NFS scores had significantly higher odds of mortality (FIB-4: OR 3.62, 95% CI 1.03–12.69; APRI: OR 2.16, 95% CI 0.88–5.30; NFS: OR 6.80, 95% CI 2.11–21.93) compared to those in the lowest tertile. The restricted cubic spline regression model showed a linear increase in the risk of in-hospital mortality with increasing liver fibrosis score. Sensitivity analysis confirmed the consistency and stability of the results across the different subgroups. Conclusion: Our study suggests that elevated liver fibrosis scores, particularly Fib-4 and NFS, are associated with higher in-hospital mortality in SIC patients. Further research, especially larger prospective studies, are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis B virus (HBV) infection remains a serious health issue, and determining the optimal time for antiviral therapy is challenging. We aimed to assess liver histological changes in patients with HBeAg-positive chronic hepatitis B (CHB) and those with HBeAg-negative CHB who had persistently normal alanine aminotransferase and to determine the association between significant liver injury and various clinical parameters. Methods: We retrospectively included, in this study, 339 treatment-naïve patients with chronic HBV infections who had persistently normal alanine aminotransferase and underwent liver biopsy from 2013 to 2023. Histologic assessment was based on the Metavir scoring system to evaluate the association between clinical characteristics and the severity of liver inflammation and fibrosis. Results: Among the included participants, 138 were HBeAg-positive and 201 were HBeAg-negative. Lower hepatitis B surface antigen (HBsAg) (P = 0.003) and higher aspartate aminotransferase (AST) (P = 0.002) levels were associated with significant necroinflammation, whereas increasing age (P = 0.004) and lower HBV DNA (P < 0.001) levels were associated with significant fibrosis in HBeAg-positive patients with normal ALT levels. Higher HBV-DNA (P = 0.001) and AST levels(P < 0.001) were associated with significant necroinflammation, and higher AST(P < 0.001) levels were associated with significant fibrosis in HBeAg-negative patients. Conclusions: A substantial proportion of patients with HBV infection who had normal ALT presented significant liver injury. HBsAg and AST were independent predictive factors for evaluating inflammation, while HBV DNA load and age were independent predictive factors for evaluating fibrosis in the HBeAg-positive group. HBV DNA load and AST were independent predictive factors for evaluating inflammation, while AST were independent predictive factors for evaluating fibrosis in the HBeAg-negative group. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions Participants with cardiovascular diseases (CVD) often exhibit liver function abnormalities, hepatic fibrosis and cirrhosis. The extent of liver fibrosis is closely related to the prognosis of CVD. However, the association between the liver fibrosis‐8 (FIB‐8) index, a marker of liver fibrosis, and all‐cause mortality in CVD participants remains unclear. This study aims to investigate the relationship between the FIB‐8 index and all‐cause mortality among individuals with CVD.A total of 1727 CVD American participants were enrolled from the National Health and Nutrition Examination Survey (NHANES) spanning from 1999 to 2018. Initially, we constructed weighted COX regression models and performed sensitivity analyses to examine the correlation between the FIB‐8 index and all‐cause mortality in CVD participants. Subsequently, we employed restricted cubic spline (RCS) to visualize their linear relationship. Finally, the stratified analyses and interaction tests of covariates were performed and presented in the forest plot.A total of 1727 participants were included in our study, with a mean age of 61.68 ± 0.47 years, with men accounting for 59.19%. After adjustment for relevant covariables, weighted COX regression models indicated that the hazard ratio (HR) and 95% confidence interval (95% CI) for the association between the FIB‐8 index and all‐cause mortality in CVD participants was 1.21 (1.12, 1.30). Sensitivity analysis was then conducted, revealing that the results remained stable. In fully adjusted model, individuals in quartiles 3 and 4 demonstrated significant statistical differences compared to the lowest FIB‐8 index quartile, with HR (95% CI) values of 1.88 (1.23, 2.87) and 2.17 (1.33, 3.53), respectively. Subsequently, RCS showed a linear relationship between the FIB‐8 index and all‐cause mortality among CVD participants. Finally, the interaction test revealed that no other covariables had significant interactions with the FIB‐8 index in this study.A positive and linear correlation was observed between the FIB‐8 index and all‐cause mortality among CVD adult participants in NHANES from 1999 to 2018. Our findings indicated that the FIB‐8 index could serve as an excellent indicator for assessing all‐cause mortality within the CVD population. The lower the FIB‐8 index, the lower the all‐cause mortality among CVD participants. [ABSTRACT FROM AUTHOR]

(1) Background: Liver damage is an important component of acute COVID-19, and the advancement of preexisting liver disease is associated with a worse prognosis; (2) Methods: A nationwide retrospective study including 7444 patients aimed to evaluate levels of selected markers of liver damage and disease advancement and their association with mortality and mechanical ventilation (MV); (3) Results: Elevation of the following markers in multivariate models were associated with increased odds of mortality: Alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), fibrosis-4 score (FIB-4), AST-to-platelet ratio index (APRI), and decreased levels of platelet count (PLT). Elevated levels of AST, LDH, APRI, FIB-4, and the AST/ALT ratio and decreased levels of PLT were associated with increased odds of MV in multivariate models. The best predictive accuracy against mortality was achieved with FIB-4 with AUC = 0.733 (95% CI, 0.718–0.749) at the optimal cut-off point of 2.764, while against MV was achieved with LDH with AUC = 0.753 (95% CI, 0.727–0.778) at the optimal cut-off point of 449.5 IU/L. (4) Conclusions: Our study confirms that the advancement of liver damage contributes to a worse prognosis in COVID-19 patients. Markers for liver damage and the advancement of liver disease can provide predictive value in clinical practice among COVID-19 patients. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the risk of liver fibrosis and associated factors with the non‐invasive fibrosis score‐4 (FIB‐4) index in patients with inflammatory arthritis using methotrexate (MTX). Methods: Patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who were followed up in the rheumatology outpatient clinic, who were on methotrexate only and for whom FIB‐4 index was could be calculated at methotrexate initiation and follow‐up were included. The FIB‐4 index was calculated according to the following formula: age (years) × AST(IU/L)/(platelet count(10 (9)/L) × √ALT(IU/L)). The patients' demographics, comorbidities, other treatments, cumulative MTX dose, and reasons for MTX cessation were assessed. For the multivariate analysis, possible factors associated with intermediate‐high risk FIB‐4 index at last visit were determined. Results: A total of 107 patients were enrolled in the study, of whom 82 (76.6%) had RA and 25 (23.4%) had PsA. At the initiation of MTX, 24 (22.4%) patients had intermediate‐high risk FIB‐4 index. Comorbidities and the rate of ≥3–4 Charlson comorbidity index were more common in patients with intermediate‐high risk FIB‐4 index. A total of 37 (34.5%) patients had intermediate‐high risk FIB‐4 index at the last visit after median 3.6 (0.3–22.06) years follow‐up. The median cumulative MTX dose was 2550 mg (1050–13.991). Cumulative MTX dose [OR 1.18 (1.01–1.33), p =.03] and diabetes mellitus [OR 4.60 (1.74–12.50), p =.002] were associated factors with intermediate‐high risk FIB‐4 index. The concomitant use of hydroxychloroquine (HCQ) was found to be a low‐risk factor for FIB‐4 index [OR 0.28 (0.10–0.78) p =.015]. Conclusion: The FIB‐4 index is a non‐invasive method that can be used in daily rheumatology practice for the evaluation and follow‐up of patients who will use methotrexate. Comorbidities and cumulative MTX dose seem to be related with the risk of liver fibrosis. Concomitant use of HCQ with MTX may reduce the risk of liver fibrosis. [ABSTRACT FROM AUTHOR]

Background and aims: Myofibroblasts, the primary producers of extracellular matrix, primarily originate from hepatic stellate cells (HSCs), and their activation plays a pivotal role in liver fibrosis. This study aimed to investigate the function of CXC motif ligand 14 (CXCL14) in the progression of liver fibrosis. Approach and results: CXCL14 knockdown significantly reduced the extent of liver fibrosis. Using Ingenuity pathway analysis and qRT‐PCR, activating transcription factor 3 (ATF3) was identified as a key upstream regulator of CXCL14 expression. Mechanistically, ATF3 was shown to bind to the CXCL14 promoter, promoting its transactivation by TGF‐β in HSCs. Notably, both global CXCL14 deletion (CXCL14−/−) and HSC/myofibroblast‐specific CXCL14 knockdown significantly attenuated liver fibrosis in mice. RNA‐seq comparisons between CXCL14−/− and WT mice highlighted Jak2 as the most significantly downregulated gene, implicating its role in the antifibrotic effects of CXCL14 suppression on HSC inactivation. Moreover, Jak2 overexpression reversed the inhibition of liver fibrosis caused by CXCL14 knockdown in vivo. Conclusions: These findings unveil a novel ATF3/CXCL14/Jak2 signalling axis in liver fibrosis, presenting potential therapeutic targets for the disease. [ABSTRACT FROM AUTHOR]

Numerous studies highlight the potential of natural antioxidants, such as those found in foods and plants, to prevent or treat nonalcoholic fatty liver disease (NAFLD). Inflammation is a key factor in the progression from high‐fat diet‐induced NAFLD to nonalcoholic steatohepatitis (NASH). Injured liver cells and immune cells release inflammatory cytokines, activating hepatic stellate cells. These cells acquire a profibrogenic phenotype, leading to extracellular matrix accumulation and fibrosis. Persistent fibrosis can progress to cirrhosis. Fatty infiltration, oxidative stress, and inflammation exacerbate fatty liver diseases. Thus, many plant‐derived antioxidants, like silymarin, silibinin, curcumin, resveratrol, berberine, and quercetin, have been extensively studied in experimental models and clinical patients with NAFLD. Experimentally, these compounds have shown beneficial effects in reducing lipid accumulation, oxidative stress, and inflammatory markers by modulating the ERK, NF‐κB, AMPKα, and PPARγ pathways. They also help decrease metabolic endotoxemia, intestinal permeability, and gut inflammation. Clinically, silymarin and silibinin have been found to reduce transaminase levels, while resveratrol and curcumin help alleviate inflammation in NAFLD patients. However, these phytocompounds exhibit poor water solubility, leading to low oral bioavailability and hindering their biological efficacy. Additionally, inconclusive clinical results highlight the need for further trials with larger populations, longer durations, and standardized protocols. Significance Statement: This review explores hepatoprotective phytochemicals for nonalcoholic fatty liver disease at the molecular level. Existing literature supports that silymarin, silibinin, resveratrol, curcumin, and berberine exhibit antioxidant and anti‐inflammatory properties by inhibiting inflammatory pathways, while also mitigating metabolic endotoxemia, intestinal permeability, and gut inflammation. However, their poor solubility and limited oral bioavailability in clinical settings reduce their potential benefits for patients with nonalcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

Liver fibrosis plays an important role in the progression of liver disease, but there is a severe shortage of direct and efficacious pharmaceutical clinical interventions. Literature research indicates that aspartic acid exhibits hepatoprotective properties. In this paper, 32 target compounds were designed and synthesized utilizing aspartic acid as the lead compound, of which 22 were new compounds not reported in the literature. These compounds were screened for their inhibitory effects on the COL1A1 promoter to assess in vitro anti-liver fibrosis activity and summarized structure–activity relationships. Four compounds exhibited superior potency with inhibition rates ranging from 66.72% to 97.44%, substantially higher than EGCG (36.46 ± 4.64%) and L-Asp (11.33 ± 0.35%). In an LPS-induced inflammation model of LX-2 cells, both 41 and 8a could inhibit the activation of LX-2 cells, reducing the expression of COL1A1, fibronectin, and α-SMA. Upon further investigation, 41 and 8a ameliorated liver fibrosis by inhibiting the IKKβ-NF-κB signaling pathway to alleviate inflammatory response. Overall, the study evaluated the anti-liver fibrosis effects of aspartic acid derivatives, identified the potency of 41, and conducted a preliminary exploration of mechanisms, laying the foundation for the discovery of novel anti-liver fibrosis agents. [ABSTRACT FROM AUTHOR]

Background and Objectives: Metabolic syndrome (MetS) is a condition marked by a complex array of physiological, biochemical, and metabolic abnormalities, including central obesity, insulin resistance, high blood pressure, and dyslipidemia (characterized by elevated triglycerides and reduced levels of high-density lipoproteins). The pathogenesis develops from the accumulation of lipid droplets in the hepatocyte (steatosis). This accumulation, in genetically predisposed subjects and with other external stimuli (intestinal dysbiosis, high caloric diet, physical inactivity, stress), activates the production of pro-inflammatory molecules, alter autophagy, and turn on the activity of hepatic stellate cells (HSCs), provoking the low grade chronic inflammation and the fibrosis. This syndrome is associated with a significantly increased risk of developing type 2 diabetes mellitus (T2D), cardiovascular diseases (CVD), vascular, renal, pneumologic, rheumatological, sexual, cutaneous syndromes and overall mortality, with the risk rising five- to seven-fold for T2DM, three-fold for CVD, and one and a half–fold for all-cause mortality. The purpose of this narrative review is to examine metabolic syndrome as a "systemic disease" and its interaction with major internal medicine conditions such as CVD, diabetes, renal failure, and respiratory failure. It is essential for internal medicine practitioners to approach this widespread condition in a "holistic" rather than a fragmented manner, particularly in Western countries. Additionally, it is important to be aware of the non-invasive tools available for assessing this condition. Materials and Methods: We conducted an exhaustive search on PubMed up to July 2024, focusing on terms related to metabolic syndrome and other pathologies (heart, Lung (COPD, asthma, pulmonary hypertension, OSAS) and kidney failure, vascular, rheumatological (osteoarthritis, rheumatoid arthritis), endocrinological, sexual pathologies and neoplastic risks. The review was managed in accordance with the PRISMA statement. Finally, we selected 300 studies (233 papers for the first search strategy and 67 for the second one). Our review included studies that provided insights into metabolic syndrome and non-invasive techniques for evaluating liver fibrosis and steatosis. Studies that were not conducted on humans, were published in languages other than English, or did not assess changes related to heart failure were excluded. Results: The findings revealed a clear correlation between metabolic syndrome and all the pathologies above described, indicating that non-invasive assessments of hepatic fibrosis and steatosis could potentially serve as markers for the severity and progression of the diseases. Conclusions: Metabolic syndrome is a multisystem disorder that impacts organs beyond the liver and disrupts the functioning of various organs. Notably, it is linked to a higher incidence of cardiovascular diseases, independent of traditional cardiovascular risk factors. Non-invasive assessments of hepatic fibrosis and fibrosis allow clinicians to evaluate cardiovascular risk. Additionally, the ability to assess liver steatosis may open new diagnostic, therapeutic, and prognostic avenues for managing metabolic syndrome and its complications, particularly cardiovascular disease, which is the leading cause of death in these patients. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the remarkable capacity of the liver to regenerate are still not completely understood. Particularly, the cross-talk between cytokines and cellular components of the process is of utmost importance because they represent potential avenues for diagnostics and therapeutics. WNT1-inducible-signaling pathway protein 1 (WISP1) is a cytokine member of the CCN family, a family of proteins that play many different roles in liver pathophysiology. WISP1 also belongs to the earliest and strongest upregulated genes in mouse livers after CCl4 intoxication and has recently been shown to be secreted by tumor cells and to bind to type 1 collagen to cause its linearization in vitro and in tumor tissue in vivo. We show that WISP1 expression is strongly induced by TGFβ, a critical cytokine in wound healing processes. Additionally, secretion of WISP1 protein by hepatic stellate is increased in cells upon TGFβ stimulation (~seven-fold increase). Furthermore, WISP1 facilitates the migration of mouse hepatic stellate cells through collagen in vitro. However, in WISP1 knockout mice, no difference in stellate cell accumulation in damaged liver tissue and no influence on fibrosis was obtained, probably because the knockout of WISP1 was compensated by other factors in vivo. [ABSTRACT FROM AUTHOR]

Background and Aims: Alpha‐1 antitrypsin deficiency is an inherited disorder caused by alpha‐1 antitrypsin (AAT) mutations. We analysed the association between alcohol intake and liver‐related parameters in individuals with the heterozygous/homozygous Pi*Z AAT variant (Pi*MZ/Pi*ZZ genotype) found in the United Kingdom Biobank and the European Alpha1 liver consortium. Methods: Reported alcohol consumption was evaluated in two cohorts: (i) the community‐based United Kingdom Biobank (17 145 Pi*MZ, 141 Pi*ZZ subjects, and 425 002 non‐carriers [Pi*MM]); and (ii) the European Alpha1 liver consortium (561 Pi*ZZ individuals). Cohort (ii) included measurements of carbohydrate‐deficient transferrin (CDT). Results: In both cohorts, no/low alcohol intake was reported by >80% of individuals, while harmful consumption was rare (~1%). Among Pi*MM and Pi*MZ individuals from cohort (i), moderate alcohol consumption resulted in a <30% increased rate of elevated transaminases and ~50% increase in elevated gamma‐glutamyl transferase values, while harmful alcohol intake led to an at least twofold increase in the abnormal levels. In Pi*ZZ individuals from both cohorts, moderate alcohol consumption had no marked impact on serum transaminase levels. Among Pi*ZZ subjects from cohort (ii) who reported no/low alcohol consumption, those with increased CDT levels more often had signs of advanced liver disease. Conclusions: Pi*MZ/Pi*ZZ genotype does not seem to markedly aggravate the hepatic toxicity of moderate alcohol consumption. CDT values might be helpful to detect alcohol consumption in those with advanced fibrosis. More data are needed to evaluate the impact of harmful alcohol consumption. [ABSTRACT FROM AUTHOR]

Background: Socioeconomic status (SES) is a driver of health disparities and chronic diseases. People with HIV (PWH) are at risk for chronic liver diseases. We evaluated the association between low SES and hepatic outcomes in PWH. Methods: We included PWH from a prospective cohort. SES was assessed by the Pampalon material and social deprivation index to classify the cohort into quintiles of deprivation. Multivariable linear regression was used to investigate associations of material and social deprivation with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) as markers of hepatic fibrosis and steatosis, respectively. Incidence of outcomes was evaluated through survival analysis. Results: Among the 804 PWH included, 45% and 72% were living in areas of the highest material and social deprivation, respectively. Materially deprived PWH were more frequently female and of non‐white ethnicity and had higher prevalence of metabolic comorbidities. After adjustments, material deprivation correlated with increased LSM (β = 1.86, 95% CI 0.53–3.17) but not with CAP (β = 6.47, 95% CI −5.55–18.49). Patients were observed for a median follow‐up of 3.8 years. Incidence of liver‐related events was higher in most materially deprived compared to most privileged PWH (hazard ratio 3.03, 95% CI 1.03–8.92), while there was no difference in extrahepatic outcomes or all‐cause mortality. Social deprivation showed no association with either LSM or clinical outcomes. Conclusions: Living in materially deprived neighbourhoods as a proxy for lower SES, is associated with LSM and liver‐related events in PWH. Future strategies should explore mechanisms underlying these relationships and whether enhanced material security improves hepatic outcomes. [ABSTRACT FROM AUTHOR]

Background and Aim: The steatosis‐associated fibrosis estimator (SAFE) score has been developed to distinguish clinically significant fibrosis in patients with steatotic liver disease (SLD). However, validation of its performance in Asian subjects is limited. This study aimed to evaluate the performance of the SAFE score in Asian subjects with biopsy‐proven SLD and in different subgroups according to age, sex, and body mass index. Methods: We retrospectively analyzed 6383 living liver donors who underwent a liver biopsy between 2005 and 2023. Of these, 1551 subjects with biopsy‐proven SLD were included. The performance of the SAFE score was evaluated using areas under the curve and compared with those of the nonalcoholic fatty liver disease fibrosis score (NFS) and fibrosis‐4 index (FIB‐4). Results: The prevalence of clinically significant fibrosis in the cohort was 2.2%. The proportion of subjects with a "low‐risk" SAFE score was the highest (91.0%), followed by those with "intermediate‐risk" (7.8%) and "high‐risk" (1.2%) scores. The prevalence of fibrosis in subjects with low‐risk, intermediate‐risk, and high‐risk scores was 1.6%, 6.6%, and 21.1%, respectively. The SAFE outperformed FIB‐4 and NFS (area under the curve: 0.70 vs 0.64 for both NFS and FIB‐4). However, it showed low diagnostic accuracy and sensitivity (27%) at the low cutoff (SAFE < 0) in subjects aged 30–39 years (fibrosis: 1.2%), despite having a high negative predictive value (0.99). Conclusion: While the SAFE score demonstrates superior performance compared with other noninvasive tests in Asian subjects with SLD, its performance varies across age groups. In younger subjects, particularly, its performance may be more limited. [ABSTRACT FROM AUTHOR]

Purpose: Hepatic fibrosis develops as a response to chronic liver injury, resulting in the formation of fibrous scars. This process is initiated and driven by collagen-producing activated myofibroblasts which reportedly express high levels of platelet derived growth factor receptor-β (PDGFRβ). We therefore regard PDGFRβ as an anchor for diagnosis and therapy. The Fibrobody® SP02SP26-ABD is a biparatopic VHH-construct targeting PDGFRβ. Here, we explore its potential as a theranostic vector for liver fibrosis. Methods: Specificity, cross-species binding, and cellular uptake of SP02SP26-ABD was assessed using human, mouse and rat PDGFRβ ectodomains and PDGFRβ-expressing cells. Cellular uptake by PDGFRβ-expressing cells was also evaluated by equipping the Fibrobody® with auristatinF and reading out in vitro cytotoxicity. The validity of PDGFRβ as a marker for active fibrosis was confirmed in human liver samples and 3 mouse models of liver fibrosis (DDC, CCl4, CDA-HFD) through immunohistochemistry and RT-PCR. After radiolabeling of DFO*-SP02SP26-ABD with 89Zr, its in vivo targeting ability was assessed in healthy mice and mice with liver fibrosis by PET-CT imaging, ex vivo biodistribution and autoradiography. Results: SP02SP26-ABD shows similar nanomolar affinity for human, mouse and rat PDGFRβ. Cellular uptake and hence subnanomolar cytotoxic potency of auristatinF-conjugated SP02SP26-ABD was observed in PDGFRβ-expressing cell lines. Immunohistochemistry of mouse and human fibrotic livers confirmed co-localization of PDGFRβ with markers of active fibrosis. In all three liver fibrosis models, PET-CT imaging and biodistribution analysis of [89Zr]Zr-SP02SP26-ABD revealed increased PDGFRβ-specific uptake in fibrotic livers. In the DDC model, liver uptake was 12.15 ± 0.45, 15.07 ± 0.90, 20.23 ± 1.34, and 20.93 ± 4.35%ID/g after 1,2,3 and 4 weeks of fibrogenesis, respectively, compared to 7.56 ± 0.85%ID/g in healthy mice. Autoradiography revealed preferential uptake in the fibrotic (PDGFRβ-expressing) periportal areas. Conclusion: The anti-PDGFRβ Fibrobody® SP02SP26-ABD shows selective and high-degree targeting of activated myofibroblasts in liver fibrosis, and qualifies as a vector for diagnostic and therapeutic purposes. [ABSTRACT FROM AUTHOR]

Purpose: The reversibility of early liver fibrosis highlights the need for improved early detection and monitoring techniques. Fibroblast activation protein (FAP) is a promising theranostics target significantly upregulated during fibrosis. This preclinical and preliminary clinical study investigated a FAP-targeted probe, gallium-68-labeled FAP inhibitor 04 ([68Ga]Ga-DOTA-FAPI-04), for its capability to visualize liver fibrosis. Methods: The preclinical study employed [68Ga]Ga-DOTA-FAPI-04 micro-positron emission tomography (PET)/computed tomography (CT) on carbon tetrachloride-induced mice model (n = 34) and olive oil-treated control group (n = 26), followed by validation of the probe's biodistribution. Hepatic uptake was correlated with fibrosis and inflammation levels, quantified through histology and serum assays. FAP and α-smooth muscle actin expression were determined by immunohistochemistry, as well as immunofluorescence. The subsequent clinical trial enrolled 26 patients with suspected or confirmed liver fibrosis to undergo [68Ga]Ga-DOTA-FAPI-04 PET/magnetic resonance imaging or PET/CT. Key endpoints included correlating [68Ga]Ga-DOTA-FAPI-04 uptake with histological inflammation grades and fibrosis stages, and evaluating its diagnostic and differential efficacy compared to established serum markers and liver stiffness measurement (LSM). Results: [68Ga]Ga-DOTA-FAPI-04 mean uptake in mice livers was notably higher than in control mice, increasing from week 6 [0.70 ± 0.11 percentage injected dose per cubic centimeter (%ID/cc)], peaking at week 10 (0.97 ± 0.15%ID/cc) and slightly reducing at week 12 (0.89 ± 0.28%ID/cc). The hepatic biodistribution and FAP expression showed a consistent trend. In the patient cohort, hepatic [68Ga]Ga-DOTA-FAPI-04 uptake presented moderate correlations with inflammation grades (r = 0.517 to 0.584, all P < 0.05) and fibrosis stages (r = 0.653 to 0.698, all P < 0.01). The average SUVmax to background ratio in the liver showed superior discriminative ability, especially between stage 0 and stage 1, outperforming LSM (area under curve 0.984 vs. 0.865). Conclusion: [68Ga]Ga-DOTA-FAPI-04 PET shows significant potential for non-invasive visualization and dynamic monitoring of liver fibrosis in both preclinical experiment and preliminary clinical trial, especially outperforming other common clinical indicators in the early stage. Trial registration: NCT04605939. Registered October 25, 2020, https://clinicaltrials.gov/study/NCT04605939 [ABSTRACT FROM AUTHOR]

Background and Aims: Because the accuracy of the Fibrosis‐4 (FIB‐4) index for predicting liver fibrosis changes with age, the need for different cut‐offs in various age groups has frequently been discussed. We developed the age‐independent score, the Fibrosis‐3 (FIB‐3) index, and have shown its usefulness in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB‐3 index to predict fibrosis progression using a large new patient cohort. Methods: The ability of the FIB‐3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB‐4 index using data from 1398 patients with MASLD enrolled in the Asia‐based clinical outcome NAFLD study. Results: The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB‐3 and FIB‐4 indices in the entire cohort. Using the single ideal cut‐offs of the indices (3.41 for FIB‐3 index and 2.01 for FIB‐4 index), the predictive accuracy of the FIB‐3 index was not significantly different from that of the FIB‐4 index among patients aged <60 years; however, the accuracy of the FIB‐3 index was significantly higher than that of the FIB‐4 index in those aged ≥60 years (0.645 and 0.529, respectively; p < 0.0001). Conclusion: The high ability of the FIB‐3 index with a single cut‐off to predict liver fibrosis in patients with MASLD was confirmed. The FIB‐3 index could serve as a useful tool for assessing liver fibrosis regardless of age. [ABSTRACT FROM AUTHOR]

Introduction The native liver survival in biliary atresia (BA) depends on various factors, and one of the crucial factors is the rate of progression of liver fibrosis after portoenterostomy, but there is no reliable investigation to assess it. This study evaluated shear wave elastography (SWE) to detect liver fibrosis in BA patients and assess its utility during follow-up. Materials and Methods This was an observational study; SWE was done preoperatively and postoperatively at 3 and 6 months. The SWE values were analyzed to determine their correlations with preoperative liver histology as well as with postoperative SWE variation between different postoperative outcomes. Results Twenty-one patients were included in the study; the preoperative SWE values were strongly correlated with liver biopsy grading (p < 0.001). At the 3 months postoperatively, SWE was done for 18 children: 12 in group A (patent bilioenteric drainage on hepatobiliary iminodiacetic acid scan) and 6 (nonpatent) in group B; mean SWE value was 12.8 and 17.3 kPa, respectively (p < 0.001). Ten children from group A underwent SWE 6 months postoperatively, and the mean value was 13.23 kPa. Conclusion The SWE values correlate with liver histology grading, suggesting a reliable alternative to biopsy. Additionally, the baseline SWE values and their trend during follow-up can provide information on the disease's progression. [ABSTRACT FROM AUTHOR]

Liver fibrosis is characterized by abnormal accumulation of extracellular matrix proteins, disrupting normal liver function. Despite its significant health impact, effective treatments remain limited. Here, we present the development of engineered lipid nanoparticles (LNPs) for targeted RNA therapeutic delivery in the liver. We investigated the therapeutic potential of modulating the G2 and S-phase expressed 1 (GTSE1) protein for treating liver fibrosis. Through screening, we identified P13 8Y LNP as a potent candidate with superior delivery efficiency and lower toxicity. Using these engineered LNPs, we successfully delivered siGTSE1 to hepatocytes, significantly reducing collagen accumulation and restoring liver function in a fibrosis animal model. Additionally, GTSE1 downregulation altered miRNA expression and upregulated hepatocyte nuclear factor 4 alpha (HNF4α). These findings suggest that therapeutic gene silencing of GTSE1 is a promising strategy for treating liver fibrosis by regenerating liver phenotypes and functions. A significant decrease in GTSE1 levels, achieved by targeted delivery of siGTSE1 using engineered LNPs, leads to reduced collagen deposition and restoration of liver function through alterations in liver fibrosis-related miRNA expression and the upregulation of hepatocyte nuclear factor 4 alpha (HNF4⍺). [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Hemoglobinopathies are the most common single gene disorders. Beta-thalassemia is one of the most common hemoglobinopathies worldwide, and a high prevalence is seen in Mediterranean region, central Asia, India, and Far East countries. Recurrent ischemic insults with parenchymal necrosis can result in hepatic fibrosis, chronic liver disease, and cirrhosis. Liver biopsy has historically been the primary means to evaluate for fibrosis and monitor disease progression, but it has significant limitations. Vibration controlled transient elastrography (VCTE) utilizing fibroscan uses an ultrasound transducer probe to create an elastic shear wave through vibrations of mild amplitude and low frequency (50Hz) which are transmitted through liver tissue. Material & Methods: Hospital based cross sectional study was conducted involving patients under 18 years of age registered for treatment of haemoglobinathies in the Department of Pediatrics, of Rajendra Institute of Medical Sciences, Ranchi during June 2021 to June 2022. Result: It was observed that AST, ALT & ALP showed some progressive increase with increase in stage of fibrosis. Higher incidence of liver fibrosis was observed as patients age advances. Conclusion: Fibroscan is a recent technology which could detect the earliest changes in hepatic pathology without invasion, it is a painless technique and correlates well with changes in hepatic enzyme leading to identification of pathologic changes. [ABSTRACT FROM AUTHOR]

Magnetic resonance elastography (MRE) is recognized as the most precise imaging technology for assessing liver fibrosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the clinical factors and pathological characteristics that may impact LSM in MASLD patients. This cross-sectional study recruited 124 patients who concurrently performed MRE, MRI-PDFF, and biopsy-proven MASLD. Linear regression models, Spearman's correlation, and subgroup analysis were employed to identify the variables affecting LSM. The AUROC (95 % CI) of MRE for diagnosing fibrosis stage ≥ 1, 2, 3, and 4 was 0.80 (0.70–0.90), 0.76 (0.66–0.85), 0.92 (0.86–0.99), and 0.99 (0.99–1.00), with corresponding cutoffs of 2.56, 2.88, 3.35, and 4.76 kPa, respectively. Multivariate analyses revealed that AST was the only independent clinical variable significantly correlated with LSM. Furthermore, LSM exhibited a notable association with the grade of lobular inflammation and hepatocellular ballooning. Subgroup analysis showed that when AST ≥ 2 ULN or inflammation grade ≥ 2, LSM of patients with early fibrosis stages showed a slight but significant increase. MRE demonstrates significant diagnostic accuracy in predicting liver fibrosis stages for MASLD patients, especially for advanced liver fibrosis and cirrhosis. However, elevated AST and the severity of liver inflammation may impact its accuracy in staging early liver fibrosis. [ABSTRACT FROM AUTHOR]

To verify the prevalence of positive Fibrosis-4 (FIB-4) score, a screening test for metabolic-associated liver disease, in a large population-based sample in the Tuscany Italian Region, and to identify sub-populations at higher risk which could be targeted by specific screening programs. Population-based survey performed in the Italian region of Tuscany, with Tuscany health informative system's administrative data. We included 594,923 subjects, of which 32% had available data for the FIB-4 calculation. The overall proportion of subjects with an FIB-4 value > 1.3, was 41.6% of those with available exams, and 12,8% of the whole population, whereas 5.4% and 1.7% had FIB-4 >2.67. In those younger than 80 years, FIB >1.3 had a 33.1% and 9.4%. People with diabetes mellitus had higher figures (52.8.% and 28.9% for FIB>1.3). Among subjects aged 70 years or over, 74.9% of those with available data and 38.4% of the general population had a FIB-4>1.3, whereas 32% and 16% had a FIB-4 > 2. The relevant proportion of FIB-4 positivity in the general population poses a significant burden for further screening with liver elastography. Targeting people with diabetes, excluding people older than 80 years and/or adopting a FIB-4 threshold of 2 in those aged more than 70 years could increase the cost-effectiveness of the screening procedures. • Individuals with a Fibrosis-4 (FIB-4 score) >1.3 should undergo liver elastography, according to Italian and international guidelines. • In a sample of Tuscan population free of liver disease, 12.8% (95%CI, 12.7%-12.8%) of subjects had FIB-4 >1.3. • If applying a 1.3 threshold for those < than 70 year old, and a 2 threshold for those ≥ 70 years, the prevalence would be 7.8% (95%CI, 7.7%-7.8%). • A higher prevalence was observed among people with diabetes: 28.9% (95% CI 28.5%-29.3%), but not in those with dyslipidemia. • Targeting people with diabetes and using 2 FIB-4 threshold in those >70 years may increase screening cost-effectivenes. [ABSTRACT FROM AUTHOR]

Background: Altered patterns of bile acids (BAs) are frequently present in liver fibrosis, and BAs function as signaling molecules to initiate inflammatory responses. Silybin meglumine (SLB-M) is widely used in treating various liver diseases including liver fibrosis. However, research on its effects on bile acid (BA) metabolism is limited. This study investigated the therapeutic effects of SLB-M on liver fibrosis and BA metabolism in a CCl4-induced murine model. Methods: A murine liver fibrosis model was induced by CCl4. Fibrosis was evaluated using HE, picrosirius red, and Masson's trichrome staining. Liver function was assessed by serum and hepatic biochemical markers. Bile acid (BA) metabolism was analyzed using LC-MS/MS. Bioinformatics analyses, including PPI network, GO, and KEGG pathway analyses, were employed to explore molecular mechanisms. Gene expression alterations in liver tissue were examined via qRT-PCR. Results: SLB-M treatment resulted in significant histological improvements in liver tissue, reducing collagen deposition and restoring liver architecture. Biochemically, SLB-M not only normalized serum liver enzyme levels (ALT, AST, TBA, and GGT) but also mitigated disruptions in both systemic and hepatic BA metabolism by increased unconjugated BAs like cholic acid and chenodeoxycholic acid but decreased conjugated BAs including taurocholic acid and taurodeoxycholic acid, compared to that in CCl4-induced murine model. Notably, SLB-M efficiently improved the imbalance of BA homeostasis in liver caused by CCl4 via activating Farnesoid X receptor. Conclusions: These findings underscore SLB-M decreased inflammatory response, reconstructed BA homeostasis possibly by regulating key pathways, and gene expressions in BA metabolism. [ABSTRACT FROM AUTHOR]

Liver fibrosis is the pathological deposition of extracellular matrix rich in fibrillar collagen within the hepatocytes in response to chronic liver injury due to various causes. As the condition advances, it can progress to cirrhosis, the late stages of which are irreversible. Multiple pathophysiological mechanisms and cell types are responsible for the progression of liver fibrosis and cirrhosis. Hepatic stellate cells and myofibroblast activation represent a key event in fibrosis. Capillarization of liver sinusoidal endothelial cells further contributes to extracellular matrix deposition and an increase in portal pressure. Macrophages and neutrophils produce inflammatory cytokines and participate in activating hepatic stellate cells. Although initially believed to be irreversible, early stages of fibrosis are now found to be reversible. Furthermore, advances in noninvasive imaging and serum studies have changed and improved how cirrhosis can be evaluated and monitored. Although there are currently no specific approved therapies to reverse liver fibrosis, management of underlying diseases has been found to halt the progression, and to an extent, even reverse liver fibrosis, preventing further liver injury and cirrhosis-related complications. [ABSTRACT FROM AUTHOR]

Background and Objectives: Pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and secondary pulmonary fibrosis (SPF), is a progressive lung disease that significantly impairs respiratory function. Accurate differentiation between IPF and SPF is crucial for effective management. This study explores the association between pulmonary fibrosis and hepatic conditions, evaluating the utility of various hemogram-derived ratios and hepatic fibrosis scores in distinguishing between IPF and SPF. Materials and Methods: We conducted a retrospective study involving patients diagnosed with IPF or SPF at the "Leon Daniello" Clinical Hospital of Pneumology in Cluj-Napoca, Romania. Pulmonary fibrosis was confirmed via imaging techniques, and hepatic steatosis and fibrosis were assessed using non-invasive scores. We analyzed clinical, laboratory, and pulmonary function data, focusing on hemogram-derived ratios and hepatic scores. Statistical analyses, including ROC curves, were used to evaluate the effectiveness of these biomarkers in differentiating IPF from SPF. Results: We included a total of 38 patients with IPF and 28 patients with SPF. Our findings revealed that IPF patients had a significantly higher FIB-4 score compared to SPF patients, suggesting increased hepatic fibrosis risk in IPF, as well as an increased RDW/PLT ratio. Conversely, SPF patients exhibited elevated PLR, PNR, and SII, reflecting a more pronounced inflammatory profile. PLR and PNR demonstrated the highest discriminatory ability between IPF and SPF, while traditional hepatic fibrosis scores showed limited differentiation capabilities. No significant differences in pulmonary function tests were observed across hepatic fibrosis risk categories. Conclusions: The study highlights the value of biomarkers like PLR and PNR in differentiating between IPF and SPF, offering additional diagnostic insights beyond traditional imaging. Integrating hepatic assessments into the management of pulmonary fibrosis could improve diagnostic accuracy and patient care. [ABSTRACT FROM AUTHOR]

Background: Numerous chemical reprogramming techniques have been reported, rendering them applicable to regenerative medicine research. The aim of our study was to evaluate the therapeutic potential of human CLiP derived from clinical specimens transplanted into a nonalcoholic steatohepatitis (NASH) mouse model of liver fibrosis. Methods: We successfully generated chemically induced liver progenitor (CLiP), which exhibited progenitor‐like characteristics, through stimulation with low‐molecular‐weight compounds. We elucidated their cell differentiation ability and therapeutic effects. However, the therapeutic efficacy of human CLiP generated from clinical samples on liver fibrosis, such as liver cirrhosis, remains unproven. Results: Following a 4 week period, transplanted human CLiP in the NASH model differentiated into mature hepatocytes and demonstrated suppressive effects on liver injury markers (i.e., aspartate transaminase and alanine transaminase). Although genes related to inflammation and fat deposition did not change in the human CLiP transplantation group, liver fibrosis‐related factors (Acta2 and Col1A1) showed suppressive effects on gene expression following transplantation, with approximately a 60% reduction in collagen fibers. Importantly, human CLiP could be efficiently induced from hepatocytes isolated from the cirrhotic liver, underscoring the feasibility of using autologous hepatocytes to produce human CLiP. Conclusion: Our findings demonstrate the effectiveness of human CLiP transplantation as a viable cellular therapy for liver fibrosis, including NASH liver. These results hold promise for the development of liver antifibrosis therapy utilizing human CLiP within the field of liver regenerative medicine. [ABSTRACT FROM AUTHOR]

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In recent years, metabolic reprogramming in liver fibrosis has become a research hotspot in the field of liver fibrosis at home and abroad. Liver fibrosis is a pathological change caused by chronic liver injury from a variety of causes. Liver fibrosis is a common pathological feature of many chronic liver diseases such as chronic hepatitis B, non‐alcoholic steatohepatitis, and autoimmune hepatitis, as well as the pathogenesis of the disease. The development of chronic liver disease into cirrhosis must go through the pathological process of liver fibrosis, in which hepatic stellate cells (HSC) play an important role. Following liver injury, HSC are activated and transdifferentiated into scar‐forming myofibroblasts, which drive the trauma healing response and which rely on the deposition of collagen‐rich extracellular matrix to maintain tissue integrity. This reaction will continue without strict control, which will lead to excessive accumulation of matrix and liver fibrosis. The mechanisms and clinical studies of liver fibrosis have been the focus of research in liver diseases. In recent years, several studies have revealed the mechanism of HSC metabolic reprogramming and the impact of this process on liver fibrosis, in which glucose metabolic reprogramming plays an important role in the activation of HSC, and it mainly meets the energy demand of HSC activation by upregulating glycolysis. Glycolysis is the process by which one molecule of glucose is broken down into two molecules of pyruvate and produces energy and lactate under anaerobic conditions. Various factors have been found to be involved in regulating the glycolytic process of HSC, including glucose transport, intracellular processing of glucose, exosome secretion, and lactate production, etc. Inhibition of the glycolytic process of HSC can be an effective strategy against liver fibrosis. Currently, the combined action of multiple targets and links of Chinese medicine such as turmeric, comfrey, rhubarb and scutellaria baicalensis against the mechanism of liver fibrosis can effectively improve or even reverse liver fibrosis. This paper summarizes that turmeric extract curcumin, comfrey extract comfreyin, rhubarb, Subtle yang yu yin granules, Scutellaria baicalensis extract oroxylin A and cardamom extract cardamomin affect liver fibrosis by regulating gluconeogenic reprogramming. Therefore, studying the mechanism of action of TCM in regulating liver fibrosis through reprogramming of glucose metabolism is promising to explore new methods and approaches for Chinese Medicine modernization research. [ABSTRACT FROM AUTHOR]