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Background: Alpha-methylacyl-CoA racemase (AMACR) deficiency is a rare peroxisomal enzyme deficiency caused by biallelic variants in the AMACR gene. This deficiency leads to the accumulation of toxic bile acid intermediates (R)-trihydroxycholestenoic acid (THCA) and (R)-dihydroxycholestenoic acid (DHCA) and pristanic acid. With less than 20 patients described in literature, the phenotype of AMACR deficiency is poorly defined and no data on the natural history are available. Results: Here we describe a cohort of 12 patients (9 adults and 3 children) with genetically confirmed AMACR deficiency (median age at diagnosis 56 years, range 3–69), followed for an average of 6 years (between 2015 and 2023). Five novel pathogenic variants are described. In 5/9 adult patients, retinitis pigmentosa was detected at a median age of 45 years (range 30–61). The median delay to diagnosis of AMACR deficiency after the diagnosis of retinitis pigmentosa was 24 years (range 0–33). All adult patients subsequently developed neurological signs and symptoms after the age of 40 years; most frequently neuropathy, ataxia and cognitive decline with prior normal cognitive functioning. One patient presented with a stroke-like episode. All adult patients showed a typical MRI pattern involving the thalami and gray matter structures of the pons and midbrain. One patient had a hepatocellular carcinoma at the time of the AMACR deficiency diagnosis and two patients suffered from gallstones. All three included children had elevated liver transaminases as single presenting sign and showed no brain MRI abnormalities. Conclusion: AMACR deficiency can be considered as an adult slowly progressive disease with a predominant neurological phenotype. The main signs comprise retinitis pigmentosa, neuropathy, ataxia and cognitive decline; stroke-like episodes may occur. Recognition of typical MRI abnormalities may facilitate prompt diagnosis. In addition, there is a risk of liver fibrosis/cirrhosis and hepatocellular carcinoma in these patients, requiring active monitoring. [ABSTRACT FROM AUTHOR]

Background: Recent studies have suggested an association between H. pylori and metabolic-disfunction associated fatty liver disease (MASLD). However, epidemiologic studies have yielded inconsistent results. We aim to evaluate the association of H. pylori and G-allele PNPLA3 in MASLD diagnosis, and markers of severity. Methods: A multi-center cross-sectional study was conducted. A total 224 functional dyspepsia (FD) patients cohort who underwent gastroscopy was selected. Biochemical, clinical parameters, ultrasound, FIB-4 score, LSM by VCTE, gastric biopsies, H. pylori status, and rs738409 PNPLA3 were evaluated. A second retrospective cohort of 86 patients with biopsy-proven MASLD who underwent gastroscopy with gastric biopsies was analyzed. Results: In the FD cohort MASLD was observed in 52%, and H. pylori-positive in 51%. H. pylori infection was associated with MASLD prevalence, but in multivariate analyses adjusted for G-allele PNPLA3, it became not significant. Then in MASLD-only dyspeptic cohort, H. pylori infection was significantly linked to elevated serum AST levels and increased liver stiffness measurements, suggesting a potential role in liver injury and fibrosis. Histopathological analysis in biopsy-proven MASLD patients further supported these findings, showing a significant association between H. pylori infection and increased NAS score, fibrosis stage, and prevalence of MASH. Notably, the combination of H. pylori infection and G-allele PNPLA3 appeared to exacerbate MASLD severity beyond individual effects. Conclusions: Our results suggest that H. pylori infection may play a role in the progression of liver injury and fibrosis in patients with MASLD, especially in those with specific genetic predispositions. [ABSTRACT FROM AUTHOR]

Summary Background Aims Methods Results Conclusions The relationships between alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with metabolic dysfunction‐associated steatotic liver disease and those with metabolic dysfunction and alcohol‐associated liver disease remain unclear.To investigate the longitudinal associations among alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with these two liver diseases.This observational cohort study included 1866 patients with metabolic dysfunction‐associated steatotic liver disease and 521 patients with metabolic dysfunction and alcohol‐associated liver disease who underwent > two health checkups over >2 years. The associations of both liver diseases with worsening non‐invasive liver fibrosis scores were assessed using the Cox regression analysis.Both liver diseases independently worsened liver fibrosis in both sexes. However, the hazard ratio for worsening liver fibrosis in females was significantly higher with metabolic dysfunction and alcohol‐associated liver disease than with metabolic dysfunction‐associated steatotic liver disease. Worsening liver fibrosis was not associated with alcohol consumption. Among males with metabolic dysfunction‐associated steatotic liver disease, the hazard ratio for worsening liver fibrosis was significantly higher in those with multiple cardiometabolic factors compared to those with a single cardiometabolic factor.Although both metabolic steatotic liver disease and metabolic alcohol‐associated liver disease were correlated with liver fibrosis progression in both sexes, the impact of alcohol consumption and cardiometabolic factors on fibrosis progression differed by sex. Cardiometabolic factors may have a stronger impact on liver fibrosis than alcohol consumption in males with metabolic dysfunction‐associated steatotic liver disease. [ABSTRACT FROM AUTHOR]

Activation of extracellular matrix–producing hepatic stellate cells (HSCs) is a key event in liver fibrogenesis. We showed that the expression of the heme-thiolate monooxygenase cytochrome P450 1B1 (CYP1B1) was elevated in human and mouse fibrotic livers and activated HSCs. Systemic or HSC-specific ablation and pharmacological inhibition of CYP1B1 attenuated HSC activation and protected male but not female mice from thioacetamide (TAA)–, carbon tetrachloride (CCl4)–, or bile duct ligation (BDL)–induced liver fibrosis. Metabolomic analysis revealed an increase in the disaccharide trehalose in CYP1B1-deficient HSCs resulting from intestinal suppression of the trehalose-metabolizing enzyme trehalase, whose gene we found to be a target of RARα. Trehalose or its hydrolysis-resistant derivative lactotrehalose exhibited potent antifibrotic activity in vitro and in vivo by functioning as an HSC-specific autophagy inhibitor, which may account for the antifibrotic effect of CYP1B1 inhibition. Our study thus reveals an endobiotic function of CYP1B1 in liver fibrosis in males, mediated by liver-intestine cross-talk and trehalose. At the translational level, pharmacological inhibition of CYP1B1 or the use of trehalose/lactotrehalose may represent therapeutic strategies for liver fibrosis. Editor's summary: Hepatic stellate cells (HSCs) are well-known actors in liver fibrosis, and a better understanding of the factors governing their activity could open up therapeutic opportunities. Tung et al. examined the role of the cytochrome P450 analog CYP1B1 in liver fibrosis, finding that its inhibition or depletion reduced liver pathology in multiple mouse models in a sex-dependent manner. The authors tied the observed antifibrotic effect in males to HSC accumulation of trehalose as a result of inhibition of trehalase in the intestine. As a test of therapeutic potential, male mice fed trehalose or nonhydrolyzable lactotrehalose in drinking water showed reduced liver fibrogenesis, with follow-up analysis of similarly treated HSCs demonstrating reduced autophagic degradation. This study suggests that the metabolite trehalose may play a sex-specific role in liver fibrosis. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Summary Background and Aims Methods Results Conclusion We aimed to characterise insulin‐like growth factor‐1 (IGF‐1) signalling in patients with advanced chronic liver disease (ACLD).Consecutive patients undergoing hepatic venous pressure gradient [HVPG] measurement were prospectively included. Clinical stages were defined as follows: probable ACLD (pACLD): liver stiffness ≥10 kPa and HVPG ≤5 mmHg, S0: mild PH (HVPG 6–9 mmHg), S1: clinically significant PH (CSPH), S2: CSPH with varices, S3: past variceal bleeding, S4: past/current non‐bleeding hepatic decompensation and S5: further decompensation.In total, 269 patients were included; 105 were compensated (pACLD: n = 18; S0: n = 30; S1: n = 20; S2: n = 37), and 164 were decompensated (S3: n = 11; S4: n = 89; S5: n = 64). Median levels of IGF‐1 decreased with progressive cirrhosis (from pACLD: 88.5 ng/mL to S5: 51.0 ng/mL; p < 0.001). Patients with CSPH had significantly lower IGF‐1 levels (63.5 ng/mL vs. 81.0 ng/mL; p = 0.001). IGF‐1 showed an independent negative association with body mass index (BMI; aB: −1.56; p < 0.001), enhanced liver fibrosis (ELF) test (aB: −8.43; p < 0.001), MELD (aB: −1.13; p = 0.042) and age (per 10 years; aB: −6.87; p < 0.001). IGF‐1 exhibited an excellent AUROC (0.856) for the prediction of liver‐related death at 6 months of follow‐up. Lower IGF‐1 (per 10 ng/mL) was linked to higher risk of (further) decompensation (0.90; 95% CI: 0.83–0.98; p = 0.016), acute‐on‐chronic liver failure (ACLF; asHR: 0.80; 95% CI: 0.68–0.93; p = 0.004) and liver‐related death (asHR: 0.76; 95% CI: 0.63–0.91; p = 0.004).Decreased levels of IGF‐1 reflect impaired hepatic function and fibrogenesis in patients with cirrhosis, which seems particularly relevant in obesity since low IGF‐1 was independently linked to high BMI. Lower IGF‐1 in cirrhosis predicts decompensation, ACLF and liver‐related death. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea syndrome (OSAS), characterized by chronic intermittent hypoxia (CIH), is an independent risk factor for aggravating non‐alcoholic steatohepatitis (NASH). The prevailing mouse model employed in CIH research is inadequate for the comprehensive exploration of the impact of CIH on NASH development due to reduced food intake observed in CIH‐exposed mice, which deviates from human responses. To address this issue, a pair‐feeding investigation with CIH‐exposed and normoxia‐exposed mice is conducted. It is revealed that CIH exposure aggravates DNA damage, leading to hepatic fibrosis and inflammation. The analysis of genome‐wide association study (GWAS) data also discloses the association between Eepd1, a DNA repair enzyme, and OSAS. Furthermore, it is revealed that CIH triggered selective autophagy, leading to the autophagic degradation of Eepd1, thereby exacerbating DNA damage in hepatocytes. Notably, Eepd1 liver‐specific knockout mice exhibit aggravated hepatic DNA damage and further progression of NASH. To identify a therapeutic approach for CIH‐induced NASH, a drug screening is conducted and it is found that Retigabine dihydrochloride suppresses CIH‐mediated Eepd1 degradation, leading to alleviated DNA damage in hepatocytes. These findings imply that targeting CIH‐mediated Eepd1 degradation can be an adjunctive approach in the treatment of NASH exacerbated by OSAS. [ABSTRACT FROM AUTHOR]

Background: Liver fibrosis can progress to end-stage cirrhosis and liver cancer. Mesenchymal stem cells (MSCs) were considered the most promising therapeutic strategy, but most of the MSCs injected intravenously traditionally are trapped in the lungs, rapidly reducing their survival ability. MSC spheroids cultured in 3D have shown higher tolerance to fluid shear stress and better survival than dissociated MSCs. Simulating the route of orthotopic liver transplantation, transplanting MSC spheroids into the liver via hepatic portal vein may impact superior therapeutic effects. Methods: In the present study, human umbilical cord-derived MSC spheroids (hUC-MSCsp) were transplanted into rhesus monkey models of liver fibrosis via B-ultrasound-guided percutaneous portal vein puncture with minimized body invasion. The therapeutic effect is evaluated through hematology, ultrasound, and pathology. To study the effect of hUC-MSCsp on gene expression in rhesus monkeys with liver injury, transcriptome sequencing analysis was performed on the livers of rhesus monkeys. The distribution of transplanted hUC-MSCsp was traced with RNA scope technology. Results: We found that hUC-MSCsp significantly restored liver function, including ALT, AST, ALB, GLOB and bilirubin. hUC-MSCsp also significantly reduced liver collagen deposition and inflammatory infiltration, and promote dismission of liver ascites. Subsequently, the therapeutic effects were further validated in TGF-β1/Smad pathway by global transcription profile. The distribution of transplanted hUC-MSCsp were also tracked, and we found that hUC-MSCsp distributed in the liver in a sphere status at 1 h after transplantation. After 16 days, the hUC-MSCsp were dispersed into dissociated cells that were predominantly distributed in the spleen, and a significant number of dissociated cells were still present in the liver. Conclusions: This study reveals the distributions of transplanted hUC-MSCsp after liver portal vein transplantation, and provides a novel approach and new insights into the molecular events of potential molecular events underlying the treatment of liver fibrosis with hUC-MSCsp. [ABSTRACT FROM AUTHOR]

Background: Alpha-1 antitrypsin deficiency (AATD) is an inherited disease, the common variant caused by a Pi*Z mutation in the SERPINA1 gene. Pi*Z AAT increases the risk of pulmonary emphysema and liver disease. Berberine (BBR) is a nature dietary supplement and herbal remedy. Emerging evidence revealed that BBR has remarkable liver-protective properties against various liver diseases. In the present study, we investigated the therapeutic effects and toxicities of BBR in Pi*Z hepatocytes and Pi*Z transgenic mice. Methods: Huh7.5 and Huh7.5Z (which carries the Pi*Z mutation) cells were treated with different concentrations of BBR for 48 hours. MTT was performed for cell viability assay. Intracellular AAT levels were evaluated by western blot. In vivo studies were carried out in wild type, native phenotype AAT (Pi*M), and Pi*Z AAT transgenic mice. Mice were treated with 50 mg/kg/day of BBR or solvent only by oral administration for 30 days. Western blot and liver histopathological examinations were performed to evaluate therapeutic benefits and liver toxicity of BBR. Results: BBR reduced intracellular AAT levels in Huh7.5Z cells, meanwhile, no Pi*Z-specific toxicity was observed. However, BBR did not reduce liver AAT load but significantly potentiated liver inflammation and fibrosis accompanying the activation of unfolded protein response and mTOR in Pi*Z mice, but not in wild type and Pi*M mice. Conclusions: BBR exacerbated liver inflammation and fibrosis specifically in Pi*Z mice. This adverse effect may be associated with the activation of unfolded protein response and mTOR. This study implicates that BBR should be avoided by AATD patients. [ABSTRACT FROM AUTHOR]

Early detection and timely intervention are essential to prevent liver fibrosis from progressing to cirrhosis or hepatocellular carcinoma. Herein, utilizing the enhanced ferritin‐manganese interaction by nanoplatinum growth, a novel ferritin‐platinum‐manganese magnetic resonance nanoplatform with RGD grafting and metformin loading (FNMMR) is developed. RGD can enhance the targeting ability of the nanoplatform toward integrin αVβ3 on activated hepatic stellate cells (aHSCs) in liver fibrosis. Systemic delivery of FNMMR shows clear degree‐dependent magnetic resonance contrast enhancement in liver fibrosis. 3D reconstruction techniques and histogram‐based features are achieved to qualitatively and quantitatively analyze the inhomogeneous liver fibrosis areas. FNMMR with catalase‐like activity can catalyze the generation of O2 to alleviate the liver fibrosis hypoxia and inhibit the expression of HIF‐1α, blocking the TGF‐β1/Smad signaling pathway. In addition, metformin shows synergy with HIF‐1α reduction in blocking the TGF‐β1/Smad pathway, effectively inhibiting the activation of HSCs and reducing collagen formation. Furthermore, FNMMR can achieve real‐time anti‐fibrotic therapy monitoring by magnetic resonance imaging. Importantly, no obvious side effects can be observed in both histological and hematology examinations. Therefore, this work presents a novel nanoplatform for accurate liver fibrosis diagnosis and synergistic anti‐fibrotic therapy with real‐time monitoring. [ABSTRACT FROM AUTHOR]

Background: The liver effects of concentrated vs. more evenly distributed moderate-to-vigorous physical activity (MVPA) patterns remain unclear. We aimed to examine the association of accelerometer-measured MVPA and different MVPA patterns with liver outcomes. Methods: Eighty-eight thousand six hundred fifty-six participants without prior liver diseases from UK Biobank were included. MVPA was measured by a wrist-worn accelerometer. Based on the guideline-based threshold (≥ 150 min/week), MVPA patterns were defined as inactive (< 150 min/week), active weekend warrior (WW; ≥ 150 min/week with ≥ 50% of total MVPA achieved within 1–2 days), and regularly active (≥ 150 min/week but not active WW) patterns. The primary outcome was incident nonalcoholic fatty liver disease (NAFLD). Results: During a median follow-up of 6.8 years, 562 participants developed NAFLD. Overall, there was a nonlinear inverse association of total MVPA with incident NAFLD (P for nonlinearity = 0.009): the risk of NAFLD rapidly decreased with the increment of MVPA (per 100 min/week increment: HR = 0.68; 95%CI, 0.57–0.81) when MVPA < 208 min/week, while moderately declined (HR = 0.91; 95%CI, 0.84–0.99) when MVPA ≥ 208 min/week. For MVPA patterns, compared with inactive group, both active WW (HR = 0.55, 95%CI, 0.44–0.67) and active regular (HR = 0.49, 95%CI, 0.38–0.63) group were associated with a similar lower risk of NAFLD. Similar results were observed for each secondary outcome, including incident severe liver diseases, incident liver cirrhosis, and liver magnetic resonance imaging-based liver steatosis and fibrosis. Conclusions: Regardless of whether MVPA was concentrated within 1 to 2 days or spread over most days of the week, more MVPA was associated with a lower risk of incident liver outcomes, including NAFLD, liver cirrhosis, liver steatosis, and fibrosis, to MVPA more evenly distributed. [ABSTRACT FROM AUTHOR]

Introduction: Liver fibrosis is a significant global health burden that lacks effective therapies. It can progress to cirrhosis and hepatocellular carcinoma (HCC). Aberrant hedgehog pathway activation is a key driver of fibrogenesis and cancer, making hedgehog inhibitors potential antifibrotic and anticancer agents. Methods: We evaluated simvastatin and STA-9090, alone and combined, in rats fed a high-fat diet (HFD) and exposed to diethylnitrosamine and thioacetamide (DENA/TAA). Simvastatin inhibits HMG-CoA reductase, depleting cellular cholesterol required for Sonic hedgehog (Shh) modification and signaling. STA-9090 directly inhibits HSP90 chaperone interactions essential for Shh function. We hypothesized combining these drugs may provide liver protective effects through complementary targeting of the hedgehog pathway. Endpoints assessed included liver function tests, oxidative stress markers, histopathology, extracellular matrix proteins, inflammatory cytokines, and hedgehog signaling components. Results: HFD and DENA/TAA caused aberrant hedgehog activation, contributing to fibrotic alterations with elevated liver enzymes, oxidative stress, dyslipidemia, inflammation, and collagen deposition. Monotherapies with simvastatin or STA-9090 improved these parameters, while the combination treatment provided further enhancements, including improved survival, near-normal liver histology, and compelling hedgehog pathway suppression. Discussion: Our findings demonstrate the enhanced protective potential of combined HMG CoA reductase and HSP90 inhibition in rats fed a HFD and exposed to DENA and TAA. This preclinical study could help translate hedgehog-targeted therapies to clinical evaluation for treating this major unmet need. [ABSTRACT FROM AUTHOR]

Objective: To investigate the diagnostic value of ultrasound elastography combined with aspartate aminotransferase to platelet ratio index (APRI), international normalized ratio/platelet ratio (INPR), and four-factor-based liver fibrosis index (FIB-4) for liver fibrosis in patients with autoimmune hepatitis (AIH). Methods: 120 AIH patients who were admitted to our hospital from January 2021 to December 2022 underwent liver biopsy and the patients were divided into significant liver fibrosis group (F2-F4, n=74) and non-significant liver fibrosis group (F0-F1, n=46) according to the Metavir evaluation system, the baseline data, ultrasound elastography shear wave velocity (SWV), FIB-4, APRI and INPR were compared between the two groups. Logistic regression was used to analyze the influencing factors of significant liver fibrosis in AIH patients. The diagnostic value of SWV combined with APRI, INPR and FIB-4 for significant liver fibrosis in AIH patients were evaluated by receiver operating characteristic (ROC) curve. Results: The biopsy results of 120 AIH patients showed that: there were 15 cases (12.50%) in F0 stage, there were 31 cases (25.83%) in F1 stage, there were 35 cases (29.17%) in F2 stage, there were 27 cases (22.50%) in F3 stage, there were 12 cases (10.00%) in F4 stage. Compared with non-significant liver fibrosis group, the INR, SWV, APRI, INPR and FIB-4 values of the patients in the significant liver fibrosis group increased, and the PLT level decreased, with statistically significant differences (P<0.05). Logistic regression analysis showed that, elevated INPR, APRI, FIB-4 and SWV were risk factors for significant liver fibrosis in AIH (P<0.05). The results of ROC curve showed that, the AUC of APRI, INPR, FIB-4 and SWV in diagnosing the degree of liver fibrosis in AIH patients was>0.700, and the combination of the four items had the highest diagnostic efficiency. Conclusion: Ultrasound electrography parameters SWV combined with APRI, INPR and FIB-4 have high diagnostic value for significant liver fibrosis in AIH patients. [ABSTRACT FROM AUTHOR]

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty acid disease (NAFLD) is caused by a build-up of fat in the liver, inducing local inflammation and fibrosis. We evaluated the effects of probiotic lactic acid-generating bacteria (LAB) derived from a traditional fermented beverage in a mouse model of NAFLD. The LAB isolated from this traditional Korean beverage were screened using the human hepatic cell line HepG2, and Lactocaseibacillus paracasei HY7207 (HY7207), which was the most effective inhibitor of fat accumulation, was selected for further study. HY7207 showed stable productivity in industrial-scale culture. Whole-genome sequencing of HY7207 revealed that the genome was 2.88 Mbp long, with 46.43% GC contents and 2778 predicted protein-coding DNA sequences (CDSs). HY7207 reduced the expression of lipogenesis and hepatic apoptosis-related genes in HepG2 cells treated with palmitic acid. Furthermore, the administration of 109 CFU/kg/day of HY7207 for 8 weeks to mice fed an NAFLD-inducing diet improved their physiologic and serum biochemical parameters and ameliorated their hepatic steatosis. In addition, HY7207 reduced the hepatic expression of genes important for lipogenesis (Srebp1c, Fasn, C/ebpa, Pparg, and Acaca), inflammation (Tnf, Il1b, and Ccl2), and fibrosis (Col1a1, Tgfb1, and Timp1). Finally, HY7207 affected the expression of the apoptosis-related genes Bax (encoding Bcl2 associated X, an apoptosis regulator) and Bcl2 (encoding B-cell lymphoma protein 2) in the liver. These data suggest that HY7207 consumption ameliorates NAFLD in mice through effects on liver steatosis, inflammation, fibrosis, and hepatic apoptosis. Thus, L. paracasei HY7207 may be suitable for use as a functional food supplement for patients with NAFLD. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions To explore the associations between cuprotosis‐related genes (CRGs) across different stages of liver disease in metabolic dysfunction‐associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC).We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD‐related HCC (n = 271) and two MAFLD single‐cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome‐wide association study (GWAS).GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD‐related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction‐associated fatty liver to metabolic‐associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD.GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T‐cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis. [ABSTRACT FROM AUTHOR]

Summary: Background: Methotrexate, an immunosuppressant used for the treatment of inflammatory bowel disease (IBD) for over 30 years, remains underused compared to thiopurines. Aims: To review the efficacy, safety, optimal dosing and delivery regimens of methotrexate in adults with IBD. Methods: We conducted a systematic review of studies involving patients with IBD treated with methotrexate from inception to August 2023. All studies were included from the MEDLINE database via PubMed. Results: For Crohn's disease, we included eight randomised controlled trials (RCTs) and 17 observational studies. Parenteral methotrexate effectively increased remission rates in steroid‐dependent patients at 25 mg/week for 16 weeks and at 15 mg/week for maintenance. Methotrexate can be used in combination with anti‐tumour necrosis factor (TNF) agents to reduce immunogenicity. Data comparing thiopurines and methotrexate remain scarce. For ulcerative colitis (UC), we included five RCTs and 10 observational studies were included; there was no evidence to support the use of methotrexate in (UC). We extracted safety data from 17 studies; mild‐to‐moderate adverse effects were common. The incidence of liver fibrosis or cirrhosis was low. Conclusion: Methotrexate is effective at inducing and maintaining remission in steroid‐refractory Crohn's disease and can reduce anti‐TNF‐induced immunogenicity when used in combination therapy. Data regarding tolerance and safety are reassuring. These findings challenge preconceived ideas on methotrexate and suggest that it is a valid first‐line conventional option for the treatment of mild‐to‐moderate Crohn's disease. [ABSTRACT FROM AUTHOR]

Background: The adenosine-adenosine receptor pathway plays important roles in the immune system and inflammation. Four adenosine receptors (i.e., A1R, A2AR, A2BR, and A3R) have been identified. However, the roles of these receptors were different in the disease progress and even play opposite roles in the same disease. This study aims to investigate the roles of A1R/A2AR/A2BR/A3R activation in liver fibrosis. Methods: Intraperitoneal injection of CCl4 into C57BL/6 mice was used to induce liver fibrosis in the models. Adenosine receptor agonists CCPA, CGS21680, BAY 60-6583, and namodenoson were used for A1R/A2AR/A2BR/A3R activation, respectively. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were used to evaluate the liver function. Hematoxylin and eosin (H&E) staining was used to investigate the pathological damage. Masson staining and Sirius Red staining were performed to evaluate the degree of collagen deposition. CCK8 and scratch assays were used to investigate the proliferation and migration ability of hepatic stellate cells (HSCs). Results: By using liver fibrosis mouse models, we observed that the A1R and A2AR agonists aggravated liver fibrosis, characterized by increasing ALT and AST levels, more serious liver pathological damage, and collagen deposition. However, the A2BR and A3R agonists alleviated liver fibrosis. Moreover, the A1R and A2AR agonist treatment promotes the proliferation and migration of HSC line LX2, while A2BR and A3R agonist treatment inhibited LX2 proliferation and migration. Consistently, A1R and A2AR agonist treatment elevated the expression of a-SMA and Col1a1 in LX2, whereas A2BR and A3R agonist treatment inhibited the expression of a-SMA and Col1a1 in LX2 cells. Additionally, 5'-N-ethylcarboxamidoadenosine (NECA), a metabolically stable adenosine analog, alleviated liver fibrosis and inhibited LX2 cell activity, proliferation, and migration. Conclusion: This study demonstrated the different roles of A1R/A2AR/A2BR/A3R during liver fibrosis development via regulating the HSC activity and proliferation. [ABSTRACT FROM AUTHOR]

The excessive deposition and cross-linking of core matrisome components typically result in abnormal remodeling of the extracellular matrix (ECM), leading to increased liver stiffness and worsening liver fibrosis. Exploring the biochemical properties of the ECM scaffold can deepen our understanding of the pathological mechanisms driving liver fibrosis and potentially facilitate the identification of therapeutic targets. While traditional sodium dodecyl sulfate (SDS)-based liver decellularization followed by proteomics can uncover the matrisome components within the ECM scaffold, it lacks the ability to reveal physicochemical characteristics like solubility. In our present study, using adult mouse liver as an example, we introduced a novel two-step workflow that combines our previously enhanced SDS (ESDS) decellularization with the conventional SDS method, enabling the identification of matrisome members with mild and/or high solubilities. Through this approach, we visualized the atlas of the mildly and highly insoluble matrisome contents in the adult mouse liver, as well as the regulatory network of highly insoluble matrisome that largely governs liver stiffness. Given the strong correlation between increased matrisome insolubility and heightened ECM stiffness, we believe that this methodology holds promise for future research focused on liver stiffness. [ABSTRACT FROM AUTHOR]

The potential of extracellular vesicles (EVs) isolated from mesenchymal stromal cells in guiding macrophages toward anti‐inflammatory immunophenotypes, has been reported in several studies. In our study, we provided experimental evidence of a distinctive effect played by Wharton Jelly mesenchymal stromal cell‐derived EVs (WJ‐EVs) on human macrophages. We particularly analyzed their anti‐inflammatory effects on macrophages by evaluating their interactions with stellate cells, and their protective role in liver fibrosis. A three‐step gradient method was used to isolate monocytes from umbilical cord blood (UCB). Two subpopulations of WJ‐EVs were isolated by high‐speed (20,000 g) and differential ultracentrifugation (110,000 g). Further to their characterization, they were designated as EV20K and EV110K and incubated at different concentrations with UCB‐derived monocytes for 7 days. Their anti‐fibrotic effect was assessed by studying the differentiation and functional levels of generated macrophages and their potential to modulate the survival and activity of LX2 stellate cells. The EV20K triggers the polarization of UCB‐derived monocytes towards a peculiar M2‐like functional phenotype more effectively than the M‐CSF positive control. The EV20K treated macrophages were characterized by a higher expression of scavenger receptors, increased phagocytic capacity and production level of interleukin‐10 and transforming growth factor‐β. Conditioned medium from those polarized macrophages attenuated the proliferation, contractility and activation of LX2 stellate cells. Our data show that EV20K derived from WJ‐MSCs induces activated macrophages to suppress immune responses and potentially play a protective role in the pathogenesis of liver fibrosis by directly inhibiting HSC's activation. [ABSTRACT FROM AUTHOR]

The fibrosis‐4 index (FIB‐4) is a noninvasive fibrosis test that is recommended for patients who are at risk of developing hepatic fibrosis. The aim of the study was to explore the correlation between FIB‐4 index and the decline of cognitive function among older patients with hypertension. The study used a cross‐sectional design to analyze data obtained from the NHANES 2011–2014. The significance of the FIB‐4 index correlation with cognitive function in individuals over the age of 60 was evaluated via multivariate regression models. The nonlinear link was described and fitted smoothed curves. There were a total of 2039 participants in the study, and those with a higher FIB‐4 index were more susceptible to developing cognitive decline. In the completely adjusted model, the association remained statistically significant between the FIB‐4 index and poor cognitive function as measured by CERAD: Total Score (OR = 0.72, 0.57−0.91), Animal Fluency Score (OR = 0.66, 0.48−0.91), and Digit Symbol Score (OR = 0.36, 0.17−0.77). A nonlinear association was found between the FIB‐4 and poor cognitive ability: Total Score, CERAD: Score Delayed Recall, Digit Symbol Score, and Animal Fluency Score. In elderly patients with hypertension, a high FIB‐4 index is correlated with an increased prevalence of cognitive decline. Hence, the FIB‐4 index could potentially serve as a valuable tool for determining individuals with hypertension who are susceptible to both liver‐related complications and cognitive impairment. [ABSTRACT FROM AUTHOR]

Alcoholic liver disease (ALD) encompasses a spectrum of manifestations from simple steatosis to steatohepatitis, progressive fibrosis, cirrhosis and liver cancer. Emerging research has spotlighted flavonoids as promising candidates for interfering the initiation, promotion and progression of ALD. Thus this paper provides a comprehensive exposition on the effects of flavonoids on ALD and elucidates the underlying mechanisms. The results show that luteolin, soyasaponin, and isoliquiritigenin have demonstrated the ability to reduce liver fat synthesis, regulate lipid metabolism, and mitigate the undesirable accumulation of fat in hepatocytes. Quercetin and genistein exhibit excellent antioxidant properties, inhibiting lipid peroxidation and oxidative stress, thereby alleviating cellular inflammation and reducing the damage caused by alcohol to hepatocytes. Naringin, cyanidin, and butein also show promise in resisting liver fibrosis. The therapeutic effects of flavonoids on ALD have been validated through cell and animal experiments. However, the application development of flavonoids in functional foods still faces challenges due to insufficient research and industrialization hurdles. [ABSTRACT FROM AUTHOR]

Aging is associated with decreased health span, and despite the recent advances made in understanding the mechanisms of aging, no antiaging drug has been approved for therapy. Therefore, strategies to promote a healthy life in aging are desirable. Previous work has shown that chronic treatment with extracellular vesicles (EVs) from young mice prolongs lifespan in old mice, but the mechanism of action of this effect on liver metabolism is not known. Here we investigated the role of treatment with EVs derived from young sedentary (EV‐C) or exercised (EV‐EX) mice in the metabolism of old mice and aimed to identify key youthful‐associated microRNA (miRNA) cargos that could promote healthy liver function. We found that aged mice treated with either EV‐C or EV‐EX had higher insulin sensitivity, higher locomotor activity resulting in longer distance traveled in the cage, and a lower respiratory exchange ratio compared to mice treated with EVs from aged mice (EV‐A). In the liver, treatment with young‐derived EVs reduced aging‐induced liver fibrosis. We identified miR‐30c in the EVs as a possible youth‐associated miRNA as its level was higher in circulating EVs of young mice. Treatment of aged mice with EVs transfected with miR‐30c mimic reduced stellate cell activation in the liver and reduced fibrosis compared to EV‐negative control by targeting Foxo3. Our results suggest that by delivering juvenile EVs to old mice, we can improve their liver health. Moreover, we identified miR‐30c as a candidate for antiaging liver therapy. [ABSTRACT FROM AUTHOR]

Schistosoma mansoni infection leads to chronic schistosomiasis and severe hepatic fibrosis. We designed a liver-targeted lipid nanoparticle (LNP) carrying siRNA against type I TGF-β receptor (TGFβRI) mRNA to treat schistosomiasis-induced liver fibrosis in BALB/c mice. Knockdown of TGFβRI by LNP-siTGFβRI reduced LX-2 cell activation in vitro and alleviated liver fibrosis in S. mansoni-infected mice. αSMA and Col1a1 fibrotic markers in the liver tissues of infected mice were significantly suppressed in the treatment groups. In the serum of the LNP-siTGFβRI-treated groups, cytokines IFNγ, IL-1α, IL-6, IL-12, RANTES (CCL5), and TNFα increased, while GM-CSF, IL-2, IL-4, IL-10, IL-13, and KC (CXCL1) decreased compared to the control. Cell proportions were significantly altered in S. mansoni-infected mice, with increased CD56d NK cells and decreased CD19+ B cells and CD4+ T cells compared to naïve mice. Following LNP-siTGFβRI treatment, CD56d NK cells were downregulated, while B and memory Th cell populations were upregulated. The density of fibrotic regions significantly decreased with LNP-siTGFβRI treatment in a dose-dependent manner, and no systemic toxicity was observed in the major organs. This targeted siRNA delivery strategy effectively reduced granulomatous lesions in schistosomiasis-induced liver fibrosis without detectable side effects. Author summary: This present study indicates that a liver-targeted lipid nanoparticles (LNPs) carrying siRNA against type I TGF-β receptor (TGFβRI) mRNA that we designed could be used to treat schistosomiasis-induced liver fibrosis. We demonstrated a liver-specific accumulation of LNPs upon intravenous injection in BALB/c mice at drug dose of 0.1 or 1 mg/kg twice a week for 4 weeks. In vitro and in vivo experiments both revealed reduced activation of HSC and alleviated liver fibrosis in S. mansoni-infected mice. The fibrotic markers αSMA and Col1a1 and serum cytokines including GM-CSF, IL-2, IL-4, IL-10, IL-13 and KC (CXCL1) from liver tissues were significantly suppressed in LNP-siTGFβRI treatment groups. FACS results indicated that following LNP-siTGFβRI treatment, CD56d NK cells showed downregulation, while B cell and memory Th cell populations were upregulated. Histological analysis showed the density of fibrotic regions were significantly decreased with LNP-siTGFβRI treatment in a dose-dependent manner and no systemic toxicity was observed in major organs. In this study, we provide a potentially targeted siRNA delivery strategy reducing granulomatous lesions for schistosomiasis-induced liver fibrosis treatment without detectable side effects. It is hoped that this study will provide effective new treatments for liver fibrosis caused by schistosomiasis in the future. [ABSTRACT FROM AUTHOR]

Background: The tumor microenvironment (TME) exerts profound effects on tumor progression and therapeutic efficacy. In hepatocellular carcinoma (HCC), the TME is enriched with cancer-associated fibroblasts (CAFs), which secrete a plethora of cytokines, chemokines, and growth factors that facilitate tumor cell proliferation and invasion. However, the intricate architecture of the TME in HCC, as well as the mechanisms driving interactions between tumor cells and CAFs, remains largely enigmatic. Methods: We analyzed 10 spatial transcriptomics and 12 single-cell transcriptomics samples sourced from public databases, complemented by 20 tumor tissue samples from liver cancer patients obtained in a clinical setting. Results: Our findings reveal that tumor cells exhibiting high levels of SPP1 are preferentially localized adjacent to hepatic stellate cells (HSCs). The SPP1 secreted by these tumor cells interacts with the CD44 receptor on HSCs, thereby activating the PI3K/AKT signaling pathway, which promotes the differentiation of HSCs into CAFs. Notably, blockade of the CD44 receptor effectively abrogates this interaction. Furthermore, in vivo studies demonstrate that silencing SPP1 expression in tumor cells significantly impairs HSC differentiation into CAFs, leading to a reduction in tumor volume and collagen deposition within the tumor stroma. Conclusions: This study delineates the SPP1-CD44 signaling axis as a pivotal mechanism underpinning the interaction between tumor cells and CAFs. Targeting this pathway holds potential to mitigate liver fibrosis and offers novel therapeutic perspectives for liver cancer management. [ABSTRACT FROM AUTHOR]

Background: The association between nonalcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) has been inconsistent, and the impact of hepatic fibrosis on this relationship remains uncertain. We investigated the association between NAFLD and the risk of new-onset AF across different age groups. Methods: A total of 3,179,582 participants from the 2009 Korean National Health Screening Program were divided into five groups based on NAFLD status: no NAFLD (fatty liver index [FLI] < 30); grade 1 NAFLD without advanced fibrosis (FLI 30–59 & BARD < 2); grade 1 NAFLD with advanced fibrosis (FLI 30–59 & BARD ≥ 2); grade 2 NAFLD without advanced fibrosis (FLI ≥ 60 & BARD < 2); and grade 2 NAFLD with advanced fibrosis (FLI ≥ 60 & BARD ≥ 2). The primary outcome was incident AF. Results: During the median follow-up of 9.3 years, 62,542 patients were diagnosed with new-onset AF. In the age- and sex-adjusted model, the risk of new-onset AF increased across NAFLD grades and fibrosis categories: grade 1 NAFLD without advanced fibrosis (hazard ratio [HR] 1.120, 95% confidence interval [CI]: 1.081–1.161); grade 1 NAFLD with advanced fibrosis (HR 1.275, 95% CI 1.251–1.300); grade 2 NAFLD without advanced fibrosis (HR 1.305, 95% CI: 1.252–1.360); and grade 2 NAFLD with advanced fibrosis (HR 1.627, 95% CI: 1.586–1.670). In the multivariate model, the excess risk of AF in patients with NAFLD and advanced fibrosis remained significant, even in participants aged 20–39 years. Conclusion: Patients with NAFLD had a higher risk of new-onset AF, which increased progressively with NAFLD severity, particularly in those aged 20–29 years. [ABSTRACT FROM AUTHOR]

Background: Recent studies have highlighted type 2 diabetes (T2DM) as a significant risk factor for the development of metabolic dysfunction-associated fatty liver disease (MAFLD). This investigation aimed to assess electroacupuncture's (EA) impact on liver morphology and function in T2DM rats, furnishing experimental substantiation for its potential to stall MAFLD progression in T2DM. Methods: T2DM rats were induced by a high-fat diet and a single intraperitoneal injection of streptozotocin, and then randomly assigned to five groups: the T2DM group, the electroacupuncture group, the metformin group, combination group of electroacupuncture and metformin, combination group of electroacupuncture and Compound C. The control group received a standard diet alongside intraperitoneal citric acid - sodium citrate solution injections. After a 6-week intervention, the effects of each group on fasting blood glucose, lipids, liver function, morphology, lipid droplet infiltration, and fibrosis were evaluated. Techniques including Western blotting, qPCR, immunohistochemistry, and immunofluorescence were employed to gauge the expression of key molecules in AMPK-associated glycolipid metabolism, insulin signaling, autophagy, and fibrosis pathways. Additionally, transmission electron microscopy facilitated the observation of liver autophagy, lipid droplets, and fibrosis. Results: Our studies indicated that hyperglycemia, hyperlipidemia and IR promoted lipid accumulation, pathological and functional damage, and resulting in hepatic steatosis and fibrosis. Meanwhile, EA enhanced the activation of AMPK, which in turn improved glycolipid metabolism and autophagy through promoting the expression of PPARα/CPT1A and AMPK/mTOR pathway, inhibiting the expression of SREBP1c, PGC-1α/PCK2 and TGFβ1/Smad2/3 signaling pathway, ultimately exerting its effect on ameliorating hepatic steatosis and fibrosis in T2DM rats. The above effects of EA were consistent with metformin. The combination of EA and metformin had significant advantages in increasing hepatic AMPK expression, improving liver morphology, lipid droplet infiltration, fibrosis, and reducing serum ALT levels. In addition, the ameliorating effects of EA on the progression of MAFLD in T2DM rats were partly disrupted by Compound C, an inhibitor of AMPK. Conclusions: EA upregulated hepatic AMPK expression, curtailing gluconeogenesis and lipogenesis while boosting fatty acid oxidation and autophagy levels. Consequently, it mitigated blood glucose, lipids, and insulin resistance in T2DM rats, thus impeding liver steatosis and fibrosis progression and retarding MAFLD advancement. [ABSTRACT FROM AUTHOR]

This article discusses the long-term outcomes of metabolic surgery compared to medical/lifestyle therapy for metabolic dysfunction-associated fatty liver disease (MAFLD) in adults with obesity and type 2 diabetes. The study found that metabolic surgery is an effective treatment for obesity, leading to weight loss and improvements in liver inflammation and fibrosis. However, there is a lack of long-term studies assessing the durability of the effects of metabolic surgery on MAFLD. The study aims to assess the long-term impacts of metabolic surgery on MAFLD compared to medical/lifestyle management. Another study compared the long-term outcomes of surgical and medical/lifestyle interventions for patients with type 2 diabetes and overweight/obesity. The study found that surgical interventions were more effective in reducing fatty liver compared to medical/lifestyle interventions. The surgical group also experienced greater weight loss, improved blood sugar levels, and higher rates of diabetes remission. However, there was no significant difference in the improvement of liver fibrosis between the two groups. The study suggests that both surgical and medical/lifestyle interventions can be effective in preventing and treating MAFLD. The document also provides information about the funding and conflicts of interest related to the study, as well as references to related studies and additional supporting information. [Extracted from the article]

The onset and progression mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are being studied. We developed and analyzed a new mouse model of obesity by combining maternal Id-like molecule (Maid) and melanocortin-4 receptor (Mc4r) gene deletions. Four mice, each at 12 and 28 weeks of age, were analyzed for each genotype: Maid gene knockout, Mc4r gene knockout, combined Mc4r and Maid gene knockout, and Mc4r gene knockout with a high-fat diet. Mice with a combined deficiency of Mc4r and Maid gene showed significantly more severe obesity compared to all other genotypes, but no liver fibrosis or a decline in metabolic status were observed. In visceral white adipose tissue, Maid and Mc4r gene knockout mice had fewer CD11c-positive cells and lower mRNA expression of both inflammatory and anti-inflammatory cytokines. Furthermore, Maid and Mc4r gene knockout mice showed lower expression of adipocytokines in visceral white adipose tissue and uncoupling protein-1 in scapular brown adipose tissue. The expression of adipocytokines and uncoupling protein-1 is regulated by sympathetic nerve signaling that contribute severe obesity in Maid and Mc4r gene knockout mice. These mechanisms contribute hyperobesity in Maid and Mc4r gene knockout mice. [ABSTRACT FROM AUTHOR]

This study aimed to estimate the hepatic and immune ameliorating potential of extracted bovine lactoferrin (LF), Selenium nanoparticles (SeNPs) or their combination (LF/SeNPs) against bleomycin (BLM) induced hepatic injury. Fifty adult male rats (160–200 g) were equally divided into five groups: (1) the saline control group, (2) BLM-injected (15 mg/kg twice a week, ip), and (3–5) groups treated orally with LF (200 mg/kg/day), SeNPs (0.0486 mg/kg/day) or LF/SeNPs combination (200.0486 mg/kg/day) for 6 weeks post BLM-intoxication. Blood and liver samples were subjected to biochemical, histopathological, and immunohistochemical analyses. The results revealed that BLM caused a significant increase in hepatic lipid peroxidation and nitric oxide, as well as serum markers of liver functions (AST, ALT and GGT activities), and levels of GM-CSF, CD4, TNF-α, IL-1β, TGF-β1, fibronectin, triglycerides, cholesterol and LDL-C. Additionally, hepatic glutathione, Na+/K+-ATPase, and glutathione peroxidase, as well as serum HDL-C, total protein and albumin levels were significantly reduced. Moreover, BLM injection resulted in marked histopathological alterations and severe expression of caspase 3. Post-treatment of BLM-intoxicated rats with LF, SeNPs or LF/SeNPs combination obviously improved the BLM-induced hepatic damages; this was achieved from the marked modulations in the mentioned parameters, besides improving the histopathological hepatic architecture. It is worth mentioning that LF/SeNPs exerted the greatest potency. In conclusion, the obtained results demonstrated that LF, SeNPs and LF/SeNPs succeeded in attenuating the BLM-induced hepatic dysfunction. Therefore, these supplements might be used to protect against drug-associated side effects. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions Data on the upregulation of Mac‐2 binding protein (M2BP) expression associated with fat accumulation in the liver are limited. Therefore, we aimed to assess the relationship between hepatic M2BP expression and changes in the liver microenvironment due to fat accumulation in patients with metabolic dysfunction associated steatotic liver disease (MASLD).Liver specimens obtained from 46 patients with MASLD were subjected to immunohistochemical staining to visualize M2BP expression in the liver. The staining intensity in the hepatocytes and sinusoidal cells was classified as high or low grade. First, the correlation between hepatic M2BP expression and microenvironmental changes caused by fat accumulation was examined. Then, the influence of hepatic M2BP expression on serum M2BP glycosylation isomer levels in patients with MASLD was evaluated.The staining grade of M2BP was higher in the sinusoidal cells than in the hepatocytes (p = 0.015). The patients with high staining grade in their hepatocytes had more severe lobular inflammation than those with low staining grade (p = 0.037). Additionally, the patients with high staining grade in their sinusoidal cells presented more severe fibrosis than those with low staining grade (p = 0.018). The staining grade in the hepatocytes correlated positively with serum M2BP glycosylation isomer levels (p = 0.023), whereas no correlation was observed between sinusoidal staining grade and serum M2BP glycosylation isomer levels (p = 0.393).Fat accumulation in patients with MASLD leads to M2BP expression in hepatocytes due to liver inflammation and that in sinusoidal cells due to fibrosis. [ABSTRACT FROM AUTHOR]

ABSTRACT Although Hepatitis C virus (HCV) infection can be cured with direct‐acting antivirals (DAA), some cured patients face a serious risk of advanced liver damage and early mortality. In order to avoid these two negative health outcomes, it is important to identify and assess related risk factors. Little is currently known about socioeconomic and behavioural factors in this context. Using data from the ANRS CO22 Hepather cohort, we tested for associations between socioeconomic and behavioural factors and (i) advanced liver fibrosis (defined as an FIB‐4 > 3.25) assessed longitudinally using a mixed‐effects logistic regression model (both the whole population and stratified on advanced liver fibrosis status at the time of HCV cure) and (ii) all‐cause mortality (Cox proportional hazards model), during post‐HCV cure follow‐up. Among 5833 participants cured of HCV, living in poverty was associated with postcure advanced liver fibrosis in participants without this diagnosis at the time of HCV cure (population attributable fraction—PAF—of 8.6%) and with mortality in the whole study population (PAF of 10.6%). The detrimental effects of unhealthy alcohol use and heavy tobacco smoking, as well as the beneficial effect of living with a stable partner were also highlighted. We highlighted the major role of poverty and behavioural factors in advanced liver fibrosis and all‐cause mortality in patients cured of HCV. Encouraging linkage to social support services and healthy behaviours after successful DAA treatment could limit morbidity and increase survival in this population.Clinical Trial Registration: ClinicalTrials.gov: NCT01953458 [ABSTRACT FROM AUTHOR]

ABSTRACT Enhanced liver fibrosis (ELF) score is a noninvasive assessment for liver fibrosis. We aimed to evaluate the performance of changes in ELF score 3 years apart in combination with liver stiffness measurement (LSM)‐hepatocellular carcinoma (HCC) score to predict HCC in chronic hepatitis B (CHB) patients. This is a prospective cohort study. Patients who underwent transient elastography (TE) examinations and at intermediate or high risk of HCC defined by LSM‐HCC score were invited to repeat the examination about 3 years later. Their serum samples at these two time points were retrieved to assess the ELF score changes. The primary endpoint was HCC. There were 445 CHB patients (males: 73.9%; mean age: 51.6 ± 10.3 years) who received two TE examinations and ELF scores. Among them, 252 (56.6%) and 193 (43.4%) patients were at intermediate and high HCC risk at first assessment defined by LSM‐HCC score, respectively. Kaplan–Meier analysis showed that the changes in ELF score could stratify the HCC risk in both intermediate‐ and high‐risk patients defined by LSM‐HCC score (p < 0.001 for intermediate‐risk group; p = 0.011 for high‐risk group). Patients remained having mild or moderate fibrosis at both assessments had the lowest risk of HCC (4.0%), followed by patients with fibrosis regressed (11.3%; p = 0.014) during a mean follow‐up of 163 months. Patients remained having or progressed to severe fibrosis were at highest risk of HCC (>20%). Consistent findings were demonstrated in patients at both intermediate and high risk of HCC defined by LSM‐HCC score. Dynamic changes in ELF score provided additional value to LSM‐HCC score for stratifying HCC risk in CHB patients. [ABSTRACT FROM AUTHOR]

Background and aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) formerly known as non-alcoholic fatty liver disease (NAFLD) is the most common liver condition globally. The FIB-4 test is used to detect fibrosis in fatty liver disease but has limited accuracy in predicting liver stiffness, resulting in high rates of false positives and negatives. The new BAST scoring system, incorporating waist circumference, AST, and BMI, has been developed to assess the presence of fibrosis in NAFLD patients. This study compares the effectiveness of BAST and FIB-4 in predicting liver fibrosis in MASLD patients. Patients and methods: The study included 140 non-diabetic MASLD patients who underwent transient elastography measurement. BAST score and FIB-4 were calculated for each patient. Patients were grouped based on fibrosis severity; F1, F2, and F3–F4. The sensitivity and specificity of the BAST score and FIB-4 were assessed using receiver operating characteristic curves. Results: The BAST score increased significantly with fibrosis progression from F1 to F3–F4. In differentiating advanced fibrosis (F2–F3) from mild/moderate fibrosis (F1–F2), the BAST score at cutoff ≤ − 0.451 showed better diagnostic performance with 90.70% sensitivity, 74.07% specificity, 84.8% PPV and 83.3% NPV compared to FIB-4 that had 60.47% sensitivity, 50.0% specificity, 65.8% PPV and 44.3% NPV. Similarly, for differentiating between F1 and F2 fibrosis, the BAST score at cutoff ≤ − 1.11 outperformed FIB-4, with 80.23% sensitivity, 79.49% specificity, 89.6% PPV and 64.6% NPV, while FIB-4 had 59.30% sensitivity, 51.28% specificity, 72.9% PPV and 36% NPV. Conclusions: The BAST score is a better predictor of liver fibrosis in MASLD compared to FIB-4, especially in cases of advanced fibrosis or cirrhosis. [ABSTRACT FROM AUTHOR]

This case report describes a 2-month-old girl with acute megakaryoblastic leukemia (AMKL) harboring the t(1;22)(p13;q13) translocation, resulting in the RBM15::MRTFA fusion gene. She presented with massive hepatosplenomegaly and liver fibrosis and achieved complete remission with chemotherapy; the liver fibrosis resolved within 2.5 months. After 12 years of follow-up, the patient remained in good health, without relapse. Reviewing the literature on eight additional similar cases of liver fibrosis, this subtype of AMKL predominantly affects female patients below 3 months of age, with a median onset at 6 weeks. High rates of severe complications were observed, with five of nine patients dying within 10 weeks of diagnosis. The authors hypothesized that the proliferation of abnormal megakaryoblasts within the liver leads to the release of profibrotic cytokines, such as TGF-b1, which induces liver fibrosis similar to that observed in transient abnormal myelopoiesis in Down syndrome. Careful monitoring of liver functions and reduced-intensity chemotherapy are recommended for this very young patient population. Nonetheless, long-term survival can be achieved with aggressive supportive care and treatment. [ABSTRACT FROM AUTHOR]

Molecular imaging holds the potential for noninvasive and accurate grading of liver fibrosis. It is limited by the lack of biomarkers that strongly correlate with liver fibrosis grade. Here, we discover the grading potential of fibroblast activation protein alpha (FAPα) for liver fibrosis through transcriptional analysis and biological assays on clinical liver samples. The protein and mRNA expression of FAPα are linearly correlated with fibrosis grade (R2 = 0.89 and 0.91, respectively). A FAPα-responsive MRI molecular nanoprobe is prepared for quantitatively grading liver fibrosis. The nanoprobe is composed of superparamagnetic amorphous iron nanoparticles (AFeNPs) and paramagnetic gadoteric acid (Gd-DOTA) connected by FAPα-responsive peptide chains (ASGPAGPA). As liver fibrosis worsens, the increased FAPα cut off more ASGPAGPA, restoring a higher T1-MRI signal of Gd-DOTA. Otherwise, the signal remains quenched due to the distance-dependent magnetic resonance tuning (MRET) effect between AFeNPs and Gd-DOTA. The nanoprobe identifies F1, F2, F3, and F4 fibrosis, with area under the curve of 99.8%, 66.7%, 70.4%, and 96.3% in patients' samples, respectively. This strategy exhibits potential in utilizing molecular imaging for the early detection and grading of liver fibrosis in the clinic. Molecular imaging holds promise for liver fibrosis grading but limited by a lack of effective biomarker. Here, the authors discover the grading potential of fibroblast activation protein alpha and design a responsive MRI nanoprobe that achieves fibrosis grading in mice models and clinical samples. [ABSTRACT FROM AUTHOR]

Introduction: Arsenic trioxide (As2O3) is an environmental contaminant that may cause hepatic injuries. As2O3-induced liver injuries are detected as an underlying cause of hepatocellular carcinoma (HCC) around the globe. The present study aimed to investigate the potential of Gardenia latifolia (GL) extracts against oxidative stress and apoptotic activity in HCC-induced rats and to explore in silico molecular docking analysis of phytocompounds of G. latifolia. Methods: The present study was designed to investigate the hepato-protective effect of ethanol and n-hexane extract of G. latifolia. Phytochemical analysis was performed using gas-chromatography-mass spectrometry (GC-MS), and the identified metabolites were used for computational docking analysis. The binding potential and inhibitory effect of the identified metabolites against inflammatory markers were assessed. Fifty male albino rats were selected for the in vivo study and were randomly divided into five groups, with 10 rats in each group. Group I is the control group. Hepatotoxicity was induced in groups II, III, IV, and V with 350 mg/kg/day of As2O3. Group II was taken as positive control, Group III and IV were treated with ethanol and n-hexane extract of G. latifolia, respectively, and Group V was treated with cisplatin 3.0 mg/kg/day. At the end of treatment, different stress and liver biomarkers were also analyzed. Results and Discussion: The quantitative phytochemical profiling revealed a high content of total flavonoid and tannins found at 5.731 ± 0.1856 mg quercetin equivalent (QE)/g and 86.31 ± 14.20 mg tannic acid equivalent (TAE)/g in G. latifolia n-hexane extract, while a significant concentration of TFC was 276.821 ± 2.19 mg gallic acid equivalent (GAE)/g, in ethanolic extract. GC-MS analysis resulted in the identification of 26 metabolites in ethanol extract while 32 metabolites in n-hexane extract, respectively. Both the extracts restored the abnormal levels of stress markers (p < 0.05) in Groups III and IV, and were comparable to the comparative control group V, which was given cisplatin as the standard drug. The histopathological examination revealed the regeneration of hepatocytes, dilated sinusoidal cells, necrosis, and distorted hepatic architecture observed in arsenic trioxide hepatotoxic liver. Among the top most identified metabolites from GC-MS analysis, stigmasterol exhibited -8.3 and -7.1 kcal/mol in silico binding affinities against cyclooxygenase-2 (COX-2), and interleukin (IL-6), respectively, while Dasycarpidan-1-methanol exhibited the best binding affinities of -6.8 and -7.2 kcal/mole against matrixmetalloprotinease (MMP)-3 and heat shock protein-90 (HSP-90), respectively. 6-AH-cAMP showed the best docking score of -7.5 kcal/mol for the vascular endothelial growth factor (VEGF) macromolecule. Metabolite Dasycarpidan-1-methanol, acetate represented drug like properties so it was further analyzed by MD simulation and stable dynamic nature of protein ligand complex was evaluated. Conclusion: In conclusion, the effective therapeutic potential of G. latifolia extracts targeted oxidative stress, increasing antioxidant activities and inhibiting inflammation and liver complications at early stages. Further research on the molecular level may further explore the anticancer potential of this plant against various types of cancers. [ABSTRACT FROM AUTHOR]

The incidence of liver disease continues to rise, encompassing a spectrum from simple steatosis or non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH), cirrhosis and liver cancer. Dietary habits in individuals with liver disease may significantly impact the treatment and prevention of these conditions. This article examines the role of chili peppers, a common dietary component, in this context, focusing on capsaicin, the active ingredient in chili peppers. Capsaicin is an agonist of the transient receptor potential vanilloid subfamily 1 (TRPV1) and has been shown to exert protective effects on liver diseases, including liver injury, NAFLD, liver fibrosis and liver cancer. These protective effects are attributed to capsaicin's anti-oxidant, anti-inflammatory, anti-steatosis and anti-fibrosis effects. This article reviewed the different molecular mechanisms of the protective effect of capsaicin on liver diseases. [ABSTRACT FROM AUTHOR]

Introduction: Si-Ni-San (SNS), a traditional Chinese medicine, is effective in treating liver fibrosis with an unclear mechanism. Although disturbance of intestinal flora and the subsequent secretion of short-chain fatty acids (SCFAs) is suggested to be involved in the progression of liver fibrosis, whether SNS produces the anti-fibrosis effect through the regulation of intestinal flora and SCFAs remains unclear. Methods: In the current study, carbon tetrachloride (CCl4)-treated mice were dosed with SNS to examine the anti-fibrotic effects and the involved mechanism. Biochemical parameters, histological staining, and analyses of fibrotic gene expression were used to evaluate the anti-fibrotic effect of SNS, while intestinal flora and SCFA content were determined by 16S rRNA and LC-MS to evaluate the mechanism. Results: In vivo results showed that SNS improved liver function, reduced hepatocyte apoptosis and FFAR2/3 expression, and restored intestinal dysbiosis and reduced PA, BA, and IsA levels. In vitro experiments showed that PA, BA, and IsA exacerbated TNF-α-induced HepG2 apoptosis. Notably, the protective effects of SNS were compromised in pseudo-sterile mice. Discussion: In conclusion, our experimental results suggest that the disturbance in intestinal flora results in elevated SCFA levels, which further exacerbates hepatocyte apoptosis in liver fibrosis, while SNS suppresses CCl4-induced liver fibrosis at least partially by reinstating intestinal flora homeostasis and reducing SCFA levels. [ABSTRACT FROM AUTHOR]

Introduction: Precise staging and classification of liver fibrosis are crucial for the hierarchy management of patients. The roles of lactylation are newly found in the progression of liver fibrosis. This study is committed to investigating the signature genes with histone lactylation and their connection with immune infiltration among liver fibrosis with different phenotypes. Methods: Firstly, a total of 629 upregulated and 261 downregulated genes were screened out of 3 datasets of patients with liver fibrosis from the GEO database and functional analysis confirmed that these differentially expressed genes (DEGs) participated profoundly in fibrosis-related processes. After intersecting with previously reported lactylation-related genes, 12 DEGs related to histone lactylation were found and narrowed down to 6 core genes using R algorithms, namely S100A6, HMGN4, IFI16, LDHB, S100A4, and VIM. The core DEGs were incorporated into the Least absolute shrinkage and selection operator (LASSO) model to test their power to distinguish the fibrotic stage. Results: Advanced fibrosis presented a pattern of immune infiltration different from mild fibrosis, and the core DEGs were significantly correlated with immunocytes. Gene set and enrichment analysis (GSEA) results revealed that core DEGs were closely linked to immune response and chemokine signaling. Samples were classified into 3 clusters using the LASSO model, followed by gene set variation analysis (GSVA), which indicated that liver fibrosis can be divided into status featuring lipid metabolism reprogramming, immunity immersing, and intermediate of both. The regulatory networks of the core genes shared several transcription factors, and certain core DEGs also presented dysregulation in other liver fibrosis and idiopathic pulmonary fibrosis (IPF) cohorts, indicating that lactylation may exert comparable functions in various fibrotic pathology. Lastly, core DEGs also exhibited upregulation in HCC. Discussion: Lactylation extensively participates in the pathological progression and immune infiltration of fibrosis. Lactylation and related immune infiltration could be a worthy focus for the investigation of HCC developed from liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: Dysregulated lipid oxidation occurs in several pathological processes characterized by cell proliferation and migration. Nonetheless, the molecular mechanism of lipid oxidation is not well appreciated in liver fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. Methods: We investigated the causes and consequences of lipid oxidation in liver fibrosis using cultured cells, animal models, and clinical samples. Results: Increased ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) expression caused increased lipid oxidation, resulting in the proliferation and migration of hepatic stellate cells (HSCs) that lead to liver fibrosis, whereas fibroblast-specific ENPP1 knockout reversing these results. Elevated ENPP1 and N6-methyladenosine (m6A) levels were associated with high expression of Wilms tumor 1 associated protein (WTAP). Mechanistically, WTAP-mediated m6A methylation of the 3'UTR of ENPP1 mRNA and induces its translation dependent of YTH domain family proteins 1 (YTHDF1). Additionally, ENPP1 could interact with hypoxia inducible lipid droplet associated (HILPDA) directly; overexpression of ENPP1 further recruits HILPDA-mediated lipid oxidation, thereby promotes HSCs proliferation and migration, while inhibition of ENPP1 expression produced the opposite effect. Clinically, increased expression of WTAP, YTHDF1, ENPP1, and HILPDA, and increased m6A mRNA content, enhanced lipid oxidation, and increased collagen deposition in human liver fibrosis tissues. Conclusions: We describe a novel mechanism in which WTAP catalyzes m6A methylation of ENPP1 in a YTHDF1-dependent manner to enhance lipid oxidation, promoting HSCs proliferation and migration and liver fibrosis. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Conclusion Metabolic dysfunction‐associated steatohepatitis (MASH) with bridging fibrosis is a critical stage in the evolution of fatty liver disease. Second harmonic generation/two‐photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence (AI) provides sensitive and reproducible quantitation of liver fibrosis. This methodology was applied to gain an in‐depth understanding of intra‐stage fibrosis changes and septa analyses in a homogenous, well‐characterised group with MASH F3 fibrosis.Paired liver biopsies (baseline [BL] and end of treatment [EOT]) of 57 patients (placebo, n = 17 and tropifexor n = 40), with F3 fibrosis stage at BL according to the clinical research network (CRN) scoring, were included. Unstained sections were examined using SHG/TPEF microscopy with AI. Changes in liver fibrosis overall and in five areas of liver lobules were quantitatively assessed by qFibrosis. Progressive, regressive septa, and 12 septa parameters were quantitatively analysed.qFibrosis demonstrated fibrosis progression or regression in 14/17 (82%) patients receiving placebo, while the CRN scoring categorised 11/17 (65%) as ‘no change’. Radar maps with qFibrosis readouts visualised quantitative fibrosis dynamics in different areas of liver lobules even in cases categorised as ‘No Change’. Measurement of septa parameters objectively differentiated regressive and progressive septa (p < .001). Quantitative changes in individual septa parameters (BL to EOT) were observed both in the ‘no change’ and the ‘regression’ subgroups, as defined by the CRN scoring.SHG/TPEF microscopy with AI provides greater granularity and precision in assessing fibrosis dynamics in patients with bridging fibrosis, thus advancing knowledge development of fibrosis evolution in natural history and in clinical trials. [ABSTRACT FROM AUTHOR]

Summary A 22‐year‐old donkey (Equus asinus) mare was presented for investigation of a 3‐day history of lethargy and anorexia. Serum biochemistry profile revealed severe increased liver‐derived enzymes. Abdominal ultrasound demonstrated several large round cysts in the liver. Broad‐spectrum antimicrobials and anti‐inflammatory therapy were started. However, exacerbation of the clinical signs occurred, and the donkey was euthanised. Necropsy and histopathological evaluation showed multiple hydatid cysts with protoscoleces from Echinocococcus spp. in the liver with replacement of parenchyma by fibrosis accompanied by liver atrophy, severe ascites and thorax effusion. The present report describes the first case of a molecularly confirmed Echinococcus equinus infection in a donkey in northern Switzerland. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a serious global health issue for which effective treatment remains elusive. Chemical-induced hepatocyte-like cells (ciHeps) have emerged as an appealing source for cell transplantation therapy, although they present several challenges such as the risk of lung thromboembolism or hemorrhage. Apoptotic vesicles (apoVs), small membrane vesicles generated during the apoptosis process, have gained attention for their role in regulating various physiological and pathological processes. In this study, we generated ciHep-derived apoVs (ciHep-apoVs) and investigated their therapeutic potential in alleviating liver fibrosis. Our findings revealed that ciHep-apoVs induced the transformation of macrophages into an anti-inflammatory phenotype, effectively suppressed the activity of activated hepatic stellate cells (aHSCs), and enhanced the survival of hepatocytes. When intravenously administered to mice with liver fibrosis, ciHep-apoVs were primarily engulfed by macrophages and myofibroblasts, leading to a reduction in liver inflammation and fibrosis. Proteomic and miRNA analyses showed that ciHep-apoVs were enriched in various functional molecules that modulate crucial cellular processes, including metabolism, signaling transduction, and ECM-receptor interactions. ciHep-apoVs effectively suppressed aHSCs activity through the synergistic inhibition of glycolysis, the PI3K/AKT/mTOR pathway, and epithelial-to-mesenchymal transition (EMT) cascades. These findings highlight the potential of ciHep-apoVs as multifunctional nanotherapeutics for liver fibrosis and provide insights into the treatment of other liver diseases and fibrosis in other organs. [ABSTRACT FROM AUTHOR]

Background: The neutrophil-to-high-density lipoprotein cholesterol ratio (NHR) has emerged as a promising biomarker for assessing inflammation and lipid dysregulation. Increasing evidence indicates that these metabolic disturbances play a crucial role in the development of metabolic dysfunction-associated steatotic liver disease(MASLD). This study aims to investigate the association between NHR, MASLD, and liver fibrosis. Methods: This cross-sectional study analyzed data from the 2017–2020 National Health and Nutrition Examination Survey (NHANES). Weighted multivariate logistic regression models were used to investigate the association between NHR and both MASLD and liver fibrosis. Smoothed curve fitting and threshold effect analysis were performed to detect potential nonlinear relationships. Subgroup analyses were conducted to assess the consistency of these associations across different groups. Results: The study involved 4,761 participants. We observed a significant positive association between NHR and MASLD (OR = 1.20, 95% CI: 1.09–1.31). However, there was no significant association between NHR and liver fibrosis (OR = 1.01; 95% CI: 0.94–1.09). The analysis of smoothed curve fitting and threshold effect revealed an inverted U-shaped relationship between NHR and MASLD, with a turning point at 5.63. Conclusion: Our findings indicate a positive correlation between elevated NHR levels and MASLD prevalence. However, we did not observe a significant association between NHR and liver fibrosis prevalence. Further prospective research is needed to validate these findings in a longitudinal setting. [ABSTRACT FROM AUTHOR]

Background: The prevalence and incidence of Nonalcoholic fatty liver disease (NAFLD) are increasing worldwide, and NAFLD has emerged as a prominent global health concern. The link between serum alanine aminotransferase (ALT) to aspartate aminotransferase (AST) ratio and NAFLD remains unclear. This study investigated the association between the ALT/AST ratio and NAFLD prevalence, including liver steatosis and fibrosis levels in the population. Methods: We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018, including 4753 participants. Subgroup analyses, stratified by age, gender, and body mass index (BMI), were performed, along with adjusted multivariable logistic regression analyses to evaluate the relationship between ALT/AST levels and the likelihood of NAFLD, liver steatosis, and hepatic fibrosis stage. A generalized additive model examined the non-linear relationship between ALT/AST and the probability of developing NAFLD. Results: Among 4753 participants, 1508 (31.73%) were diagnosed with NAFLD. Significant positive correlations between ALT/AST and NAFLD risk were found across all models. In addition, the subgroup analysis by gender, age, and BMI suggested that ALT/AST showed a positive correlation with NAFLD. The ALT/AST ratio was positively correlated with the degree of liver steatosis and liver fibrosis. The correlation between ALT/AST and the incidence of NAFLD showed a non linear pattern. In women, the non-linear trend is particularly evident, showing an inverted U-shaped curve with an inflection point of 1.302. A receiver operating characteristic (ROC) analysis showed that the predictive value of ALT/AST for NAFLD was better than that of traditional liver enzyme parameters. Conclusion: A higher ALT/AST ratio was independently associated with a significantly higher risk of NAFLD and liver fibrosis within American cohorts. This link is robust among females, children, and adolescents. ALT/AST ratio can be used as a simple and effective noninvasive biomarker to identify individuals with high risk of NAFLD. [ABSTRACT FROM AUTHOR]

Biomolecular condensates formed by liquid-liquid phase separation (LLPS) have become an extensive mechanism of macromolecular metabolism and biochemical reactions in cells. Large molecules like proteins and nucleic acids will spontaneously aggregate and assemble into droplet-like structures driven by LLPS when the physical and chemical properties of cells are altered. LLPS provides a mature molecular platform for innate immune response, which tightly regulates key signaling in liver immune response spatially and physically, including DNA and RNA sensing pathways, inflammasome activation, and autophagy. Take this, LLPS plays a promoting or protecting role in a range of liver diseases, such as viral hepatitis, non-alcoholic fatty liver disease, liver fibrosis, hepatic ischemia-reperfusion injury, autoimmune liver disease, and liver cancer. This review systematically describes the whole landscape of LLPS in liver innate immunity. It will help us to guide a better-personalized approach to LLPS-targeted immunotherapy for liver diseases. [ABSTRACT FROM AUTHOR]

Activin A and hepatic stellate cells (HSCs) are involved in tissue repair and fibrosis in liver injury. This study investigated the impact of activin A on HSC activation and migration. A microfluidic D4-chip was used for examining the cell migration of mouse hepatic stellate cell line MHSteC. The analysis of differentially expressed genes revealed that activin βA (Inhba), activin receptor type 1A (Acvr1a) and type 2A (Acvr2a) mRNAs were more significantly expressed in human HSCs than in the hepatocytes. Moreover, activin A promoted MHSteC proliferation and induced MHSteC migration. Furthermore, the MHSteCs treated with activin A exhibited increased levels of migration-related proteins, N-cadherin, Vimentin, α-SMA, MMP2 and MMP9, but a decreased level of E-cadherin. Additionally, activin A treatment significantly increased the p-Smad3 levels and p-Smad3/Smad3 ratio in the MHSteCs, and the Smad3 inhibitor SIS3 attenuated activin A-induced MHSteC proliferation and migration. Simultaneously, activin A increased the calcium levels in the MHSteCs, and the migratory effects of activin A on MHSteCs were weakened by the intracellular calcium ion-chelating agent BAPTA-AM. These data indicate that activin A can promote MHSteC activation and migration through the canonical Smad3 signaling and calcium signaling. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Conclusions Metabolic dysfunction‐associated steatotic liver disease (MASLD) recurrence after liver transplantation (LT) seems unavoidable and gradual. We aimed to evaluate the diagnostic accuracy in the post‐LT setting of patients transplanted for metabolic dysfunction‐associated steatohepatitis (MASH) of recurrent hepatic steatosis and fibrosis identified with FibroScan, compared to biopsy findings.This prospective cohort study included adults transplanted for MASH between 2010 and 2022 in three LT centres in Spain who underwent FibroScan and biopsy at least 1‐year after LT.In total, 44 patients transplanted for MASH after LT were included. The median time from LT to biopsy and FibroScan was 24.5 (interquartile range [IQR]:16–46) and 26.0 (IQR: 16.8–41.5) months, respectively. The median time between biopsy and FibroScan was 2.0 (IQR: 0–5) months. On FibroScan, significant steatosis was diagnosed in about half of the patients (n = 21, 47.7%), yet advanced fibrosis in only two cases (4.6%). On biopsy, a quarter of biopsied patients (n = 11, 25%) had a MASH diagnosis, two (4.6%) with significant fibrosis and one (2.3%) with cirrhosis. All patients with liver stiffness measurement (LSM) values <8 kPa (n = 35, 79.5%) had a fibrosis stage ≤F1 (negative predictive value = 100%). The combination of post‐LT hypertension (odds ratio [OR]: 12.0, 95% confidence interval [CI]: 1.8–80.4, p = .010) and post‐LT dyslipidaemia (OR: 7.9, 95% CI: 1.3–47.1, p = .024) with LSM (OR: 1.7, 95% CI: 1.1–2.8, p = .030) was independently associated with MASLD.Although biopsy remains the gold standard for detecting fibrosis, our results suggest that LSM values <8 kPa after LT for MASH are strongly correlated with absence of significant/advanced fibrosis. [ABSTRACT FROM AUTHOR]

Background: Hepatic fibrosis, a prevalent chronic liver condition, involves excessive extracellular matrix production associated with aberrant wound healing. Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis, activated by inflammatory factors such as sphingosine 1-phosphate (S1P). Despite S1P's involvement in fibrosis, its specific role and downstream pathway in HSCs remain controversial. Methods: In this study, we investigated the regulatory role of S1P/S1P receptor (S1PR) in Hippo-YAP activation in both LX-2 cell lines and primary HSCs. Real-time PCR, western blot, pharmacological inhibitors, siRNAs, and Rho activity assays were adopted to address the molecular mechanisms of S1P mediated YAP activation. Results: Serum and exogenous S1P significantly increased the expression of YAP target genes in HSCs. Pharmacologic inhibitors and siRNA-mediated knockdowns of S1P receptors showed S1P receptor 2 (S1PR2) as the primary mediator for S1P-induced CTGF expression in HSCs. Results using siRNA-mediated knockdown, Verteporfin, and Phospho-Tag immunoblots showed that S1P-S1PR2 signaling effectively suppressed the Hippo kinases cascade, thereby activating YAP. Furthermore, S1P increased RhoA activities in cells and ROCK inhibitors effectively blocked CTGF induction. Cytoskeletal-perturbing reagents were shown to greatly modulate CTGF induction, suggesting the important role of actin cytoskeleton in S1P-induced YAP activation. Exogeneous S1P treatment was enough to increase the expression of COL1A1 and α-SMA, that were blocked by YAP specific inhibitor. Conclusions: Our data demonstrate that S1P/S1PR2-Src-RhoA-ROCK axis leads to Hippo-YAP activation, resulting in the up-regulation of CTGF, COL1A1 and α-SMA expression in HSCs. Therefore, S1PR2 may represent a potential therapeutic target for hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Cirrhosis, a pathological stage that develops from various chronic liver diseases, is characterized by liver fibrosis, pseudolobular formation, and chronic inflammation. When it progresses to the decompensated phase, the mortality rate of cirrhosis can reach 80%. The role of gut microbiota in the progression of liver diseases has received significant attention. Numerous studies have shown that regulating gut microbiota has significant therapeutic effects on preventing and reversing liver cirrhosis. This article reviewed the mechanisms by which gut microbiota influence liver cirrhosis, explaining the effective therapeutic effects of traditional Chinese medicine. Through multi-directional regulation involving signaling pathways, gut microbiota diversity, and restoration of intestinal barrier function, traditional Chinese medicine has been promising in ameliorating liver cirrhosis, providing treatment options and pharmacological guidance for the occurrence and development of liver cirrhosis. [ABSTRACT FROM AUTHOR]