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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: 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]

Background & Aims: Cystic fibrosis (CF) is considered a multisystemic disorder in which CF‐associated liver disease (CFLD) is the third most common cause of mortality. Currently, no effective treatment is available for CFLD because its pathophysiology is still unclear. Interestingly, CFLD exhibits identical vascular characteristics as non‐cirrhotic portal hypertension, recently classified as porto‐sinusoidal vascular disorders (PSVD). Methods: Since endothelial cells (ECs) are an important component in PSVD, we performed single‐cell RNA sequencing (scRNA‐seq) on four explant livers from CFLD patients to identify differential endothelial characteristics which could contribute to the disease. We comprehensively characterized the endothelial compartment and compared it with publicly available scRNA‐seq datasets from cirrhotic and healthy livers. Key gene signatures were validated ex vivo on patient tissues. Results: We found that ECs from CF liver explants are more closely related to healthy than cirrhotic patients. In CF patients we also discovered a distinct population of liver sinusoidal ECs—coined CF LSECs—upregulating genes involved in the complement cascade and coagulation. Finally, our immunostainings further validated the predominant periportal location of CF LSECs. Conclusions: Our work showed novel aspects of human liver ECs at the single‐cell level thereby supporting endothelial involvement in CFLD, and reinforcing the hypothesis that ECs could be a driver of PSVD. Therefore, considering the vascular compartment in CF and CFLD may help developing new therapeutic approaches for these diseases. [ABSTRACT FROM AUTHOR]

Background and Aims: Exercise is recommended for the management of metabolic dysfunction‐associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training. Methods: We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12–20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI‐measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness. Results: Eighty‐eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m2. Following the intervention, exercise had ~5‐fold (OR [95%CI]: 4.86 [1.72, 13.8], p =.002) greater odds of ≥30% relative reduction in MRI‐measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (V̇O2peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight). Conclusion: Exercise training led to clinically meaningful improvements in surrogate serum‐ and imaging‐based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight‐neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD. [ABSTRACT FROM AUTHOR]

Malnutrition is a public health epidemic mainly targeting poverty‐stricken people, young ones, older people, pregnant women, and individuals with metabolic disorders. Severe malnutrition is linked with several metabolic defects, such as hepatic dysfunction, hypertension, cardiovascular disease, and osteoarthritis. The proper functioning of the liver plays a crucial role in ensuring the supply of nutrients to the body. Consequently, inadequate nutrition can lead to severe periportal hepatic steatosis due to compromised mitochondrial and peroxisome functions. Reduced protein intake disrupts essential metabolic processes like the TCA cycle, oxidative phosphorylation, and β‐oxidation, ultimately affecting ATP production. Furthermore, this can trigger a cascade of events, including disturbances in amino acid metabolism, iron metabolism, and gut microbiota, which activate genes involved in de novo lipogenesis, leading to the accumulation of lipids in the liver. The condition, in prolonged cases, progresses to steatohepatitis and liver fibrosis. Limited therapeutic solutions are available; however, few dietary supplements and drugs have demonstrated positive effects on the growth and health of malnourished individuals. These supplements improve parameters such as inflammatory and oxidative status, reduce triglyceride accumulation, enhance insulin sensitivity, and downregulate gene expression in hepatic lipid metabolism. This review elucidates the various mechanisms involved in malnutrition‐associated steatohepatitis and provides an overview of the available approaches for treating this condition. [ABSTRACT FROM AUTHOR]

Fatty liver, which is induced by abnormal lipid metabolism, is one of the most common causes of chronic liver disease globally and causes liver fibrosis. During this process, bone marrow-derived mesenchymal stromal cells (BMSCs) and hepatic stellate cells (HSCs) migrate toward the injured liver and participate in fibrogenesis by transdifferentiating into myofibroblasts. S100A8/A9 is a powerful inducer of cell migration and is involved in liver injury. But there are few reports about the effects of S100A8/A9 on BMSC/HSC migration. In the current study, we found that S100A8/A9 expression was increased during fatty liver injury/fibrogenesis. Moreover, S100A8/A9 expression had a positive correlation with fibrosis marker gene expressions in the injured liver. S100A8/A9 was mainly produced by neutrophils in the fibrotic liver. In vitro, neutrophil-secreted S100A8/A9 promoted BMSC/HSC migration via remodeling of microfilaments. Using specific siRNA and inhibitor, we proved that S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. Moreover, S100A8/A9 knock-down alleviated liver injury and fibrogenesis in vivo, while injection of S100A9 neutralizing antibody performed similar roles. We proved that S100A8/A9 was involved in liver injury and fibrogenesis via inducing BMSC/HSC migration. Our research reveals a new mechanism underlying BMSC/HSC migration in liver fibrosis and suggests S100A8/A9 as a potential therapeutic target of liver fibrosis. Key messages: S100A8/A9 is secreted by neutrophils and increased in fatty liver injury. Neutrophil-secreted S100A8/A9 is a mediator of BMSC/HSC migration in vitro. S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. S100A8/A9 blockade alleviates liver injury and fibrogenesis in vivo. [ABSTRACT FROM AUTHOR]

Background: The development of graft fibrosis after pediatric liver transplantation (PLT) remains a major concern as it can lead to graft failure and ultimately graft loss. Elastography is a non‐invasive method to assess liver fibrosis, but its role in the posttransplant setting is unclear. The aim of our study was to evaluate shear wave elastography (SWE) in the assessment of liver fibrosis after PLT, including split‐liver recipients. Methods: We retrospectively analyzed data from PLT recipients who underwent surveillance liver biopsy and concurrent 2D‐SWE during the study period from April 2018 to July 2021. Spearman's correlation was used to compare histologic fibrosis stages with liver stiffness measurements (LSM) by 2D‐SWE. AUROC analysis was performed to evaluate the performance. One sample t‐test was used to compare results with reference values of healthy children. Results: 62 cases were included. 29% showed histologic fibrosis. LSM by 2D‐SWE were feasible in all children regardless of age or graft type. There was a significant correlation between LSM and fibrosis stage for all three scoring systems used (Ishak, p = 0.003; METAVIR, p = 0.005; LAF Score, p = 0.003). Patients with a history of biliary complications had increased liver stiffness (p = 0.015). The AUROC of 2D‐SWE for predicting significant liver graft fibrosis was 0.81. Liver stiffness after PLT without graft fibrosis was higher than in healthy subjects, but comparable to that in children with chronic liver disease without fibrosis. Conclusion: 2D‐SWE can reliably detect children with significant liver graft fibrosis, even in split‐liver recipients. This study demonstrates the value of a non‐invasive tool for fibrosis staging after PLT. 2D‐SWE has the potential to improve long‐term outcomes after PLT and to reduce the number of surveillance liver biopsies. But elastography is not a substitute for liver biopsy. [ABSTRACT FROM AUTHOR]

Digital pathology has enabled the noninvasive quantification of pathological parameters. In addition, the combination of digital pathology and artificial intelligence has enabled the analysis of a vast amount of information, leading to the sharing of much information and the elimination of knowledge gaps. Fibrosis, which reflects chronic inflammation, is the most important pathological parameter in chronic liver diseases, such as viral hepatitis and metabolic dysfunction-associated steatotic liver disease. It has been reported that the quantitative evaluation of various fibrotic parameters by digital pathology can predict the prognosis of liver disease and hepatocarcinogenesis. Liver fibrosis evaluation methods include 1 fiber quantification, 2 elastin and collagen quantification, 3 s harmonic generation/two photon excitation fluorescence (SHG/TPE) microscopy, and 4 Fibronest™.. In this review, we provide an overview of role of digital pathology on the evaluation of fibrosis in liver disease and the characteristics of recent methods to assess liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: The influence of alcohol intake on metabolic dysfunction‐associated fatty liver disease (MAFLD) development and remission remains unclear; thus, we aimed to investigate their longitudinal associations. Methods: This observational cohort study included 6349 patients who underwent more than two health check‐ups over >2 years between April 2013 and March 2021. Generalized estimation equations were used to analyse the longitudinal associations between changes in alcohol intake and MAFLD according to repeated measures at baseline and the most recent stage. Results: The MAFLD development and remission rates were 20.4 and 5.1 and 9.1 and 4.7% in men and women, respectively. Although alcohol consumption was not a significant factor for MAFLD development, consuming 0.1–69.9 g/week (odds ratio [OR]: 0.672, 95% confidence interval [CI]: 0.469–0.964, p <.05) and ≥280 g/week were significant factors for MAFLD development in males (OR: 1.796, 95% CI: 1.009–3.196, p <.05) and females (OR: 16.74, 95% CI: 3.877–72.24, p <.001). Regardless of quantity and frequency, alcohol consumption was not a significant factor for MAFLD remission. Several noninvasive liver fibrosis scores were significantly associated with alcohol intake quantity and frequency in males with MAFLD development and remission (p <.05). The nonalcoholic fatty liver disease fibrosis score differed significantly between males with and without reduced alcohol intake (p <.05) who showed MAFLD remission. Conclusions: Although the influence of alcohol intake on MAFLD development and remission differed, alcohol consumption was not beneficial for MAFLD remission in either sex. Alcohol intake reduction or cessation is recommended to prevent liver fibrosis, even in those who achieve MAFLD remission. [ABSTRACT FROM AUTHOR]

The hepatic sinusoids are composed of liver sinusoidal endothelial cells (LSECs), which are surrounded by hepatic stellate cells (HSCs) and contain liver-resident macrophages called Kupffer cells, and other patrolling immune cells. All these cells communicate with each other and with hepatocytes to maintain sinusoidal homeostasis and a spectrum of hepatic functions under healthy conditions. Sinusoidal homeostasis is disrupted by metabolites, toxins, viruses, and other pathological factors, leading to liver injury, chronic liver diseases, and cirrhosis. Alterations in hepatic sinusoids are linked to fibrosis progression and portal hypertension. LSECs are crucial regulators of cellular crosstalk within their microenvironment via angiocrine signaling. This review discusses the mechanisms by which angiocrine signaling orchestrates sinusoidal homeostasis, as well as the development of liver diseases. Here, we summarise the crosstalk between LSECs, HSCs, hepatocytes, cholangiocytes, and immune cells in health and disease and comment on potential novel therapeutic methods for treating liver diseases. [ABSTRACT FROM AUTHOR]

The worldwide epidemics of obesity, hypertriglyceridemia, dyslipidaemia, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) represent a major economic burden on healthcare systems. Patients with at-risk MASH, defined as MASH with moderate or significant fibrosis, are at higher risk of comorbidity/mortality, with a significant risk of cardiovascular diseases and/or major adverse liver outcomes. Despite a high unmet medical need, there is only one drug approved for MASH. Several drug candidates have reached the phase III development stage and could lead to several potential conditional drug approvals in the coming years. Within the armamentarium of future treatment options, FGF21 analogues hold an interesting position thanks to their pleiotropic effects in addition to their significant effect on both MASH resolution and fibrosis improvement. In this review, we summarise preclinical and clinical data from FGF21 analogues for MASH and explore additional potential therapeutic indications. [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 (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as 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 T2D 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]

Steatotic liver disease (SLD), characterized by elevated liver fat content (LFC), is influenced by genetics and diet. However, whether diet has a differential effect based on genetic risk is not well-characterized. We aimed to determine how genetic factors interact with diet to affect SLD in a large national biobank. We included UK Biobank participants with dietary intake measured by 24-hour recall and genotyping. The primary predictors were dietary pattern, PNPLA3 -rs738409-G, TM6SF2 -rs58542926-T, a 16-variant hepatic steatosis polygenic risk score (PRS), and gene-environment interactions. The primary outcome was LFC, and secondary outcomes were iron-controlled T1 time (cT1, a measure of liver inflammation and fibrosis) and liver-related events/mortality. A total of 21,619 participants met inclusion criteria. In non-interaction models, Mediterranean diet and intake of fruit/vegetables/legumes and fish associated with lower LFC, while higher red/processed meat intake and all genetic predictors associated with higher LFC. In interaction models, all genetic predictors interacted with Mediterranean diet and fruit/vegetable/legume intake, while the steatosis PRS interacted with fish intake and the TM6SF2 genotype interacted with red/processed meat intake, to affect LFC. Dietary effects on LFC were up to 3.8-fold higher in PNPLA3 -rs738409-GG vs. –CC individuals, and 1.4-3.0-fold higher in the top vs. bottom quartile of the steatosis PRS. Gene-diet interactions were stronger in participants with vs. without overweight. The steatosis PRS interacted with Mediterranean diet and fruit/vegetable/legume intake to affect cT1 and most dietary and genetic predictors associated with risk of liver-related events or mortality by age 70. Effects of diet on LFC and cT1 were markedly accentuated in patients at increased genetic risk for SLD, implying dietary interventions may be more impactful in these populations. Genetic variants and diet both influence risk of hepatic steatosis, inflammation/fibrosis, and hepatic decompensation; however, how gene-diet interactions influence these outcomes has previously not been comprehensively characterized. We investigated this topic in the community-based UK Biobank and found that genetic risk and dietary quality interacted to influence hepatic steatosis and inflammation/fibrosis on liver MRI, so that the effects of diet were greater in people at elevated genetic risk. These results are relevant for patients and medical providers because they show that genetic risk is not fixed (i.e. modifiable factors can mitigate or exacerbate this risk) and realistic dietary changes may result in meaningful improvement in liver steatosis and inflammation/fibrosis. As genotyping becomes more routinely used in clinical practice, patients identified to be at high baseline genetic risk may benefit even more from intensive dietary counseling than those at lower risk, though future prospective studies are required. [Display omitted] • Poor diet quality and specific genetic alleles are associated with steatotic liver disease. • Diet has a much greater impact on hepatic steatosis in those at higher genetic risk. • These effects were seen for both liver fat content and iron-controlled T1 time (a measure of fibrosis and inflammation). • Hence, dietary interventions may have a greater impact in populations at higher genetic risk. [ABSTRACT FROM AUTHOR]

Cystic fibrosis-related liver disease (CFLD) is a chronic cholangiopathy that increases morbidity and mortality in patients with CF. Current treatments are unsatisfactory, and incomplete understanding of CFLD pathogenesis hampers therapeutic development. We have previously shown that mouse CF cholangiocytes respond to lipopolysaccharide with excessive inflammation. Thus, we investigated the role of the gut-liver axis in the pathogenesis of CFLD. Wild-type (WT), whole-body Cftr knockout (CFTR-KO) and gut-corrected (CFTR-KO-GC) mice were studied. Liver changes were assessed by immunohistochemistry and single-cell transcriptomics (single-cell RNA sequencing), inflammatory mediators were analysed by proteome array, faecal microbiota by 16S ribosomal RNA sequencing and gut permeability by FITC-dextran assay. The livers of CFTR-KO mice showed ductular proliferation and periportal inflammation, whereas livers of CFTR-KO-GC mice had no evident pathology. Single-cell RNA sequencing analysis of periportal cells showed increased presence of neutrophils, macrophages and T cells, and activation of pro-inflammatory and pathogen-mediated immune pathways in CFTR-KO livers, consistent with a response to gut-derived stimuli. CFTR-KO mice exhibited gut dysbiosis with enrichment of Enterobacteriaceae and Enterococcus spp., which was associated with increased intestinal permeability and mucosal inflammation, whereas gut dysbiosis and inflammation were absent in CFTR-KO-GC mice. Treatment with nonabsorbable antibiotics ameliorated intestinal permeability and liver inflammation in CFTR-KO mice. Faecal microbiota transfer from CFTR-KO to germ-free WT mice did not result in dysbiosis nor liver pathology, indicating that defective intestinal CFTR is required to maintain dysbiosis. Defective CFTR in the gut sustains a pathogenic microbiota, creates an inflammatory milieu, and alters intestinal permeability. These changes are necessary for the development of cholangiopathy. Restoring CFTR in the intestine or modulating the microbiota could be a promising strategy to prevent or attenuate liver disease. Severe cystic fibrosis-related liver disease (CFLD) affects 10% of patients with cystic fibrosis (CF) and contributes to increased morbidity and mortality. Treatment options remain limited due to a lack of understanding of disease pathophysiology. The cystic fibrosis transmembrane conductance regulator (CFTR) mediates Cl− and HCO 3 − secretion in the biliary epithelium and its defective function is thought to cause cholestasis and excessive inflammatory responses in CF. However, our study in Cftr -knockout mice demonstrates that microbial dysbiosis, combined with increased intestinal permeability caused by defective CFTR in the intestinal mucosa, acts as a necessary co-factor for the development of CFLD-like liver pathology in mice. These findings uncover a major role for the gut microbiota in CFLD pathogenesis and call for further investigation and clinical validation to develop targeted therapeutic strategies acting on the gut-liver axis in CF. [Display omitted] • The CF gut microbiota features reduced diversity and increased Enterobacteriales. • Gut dysbiosis in CF is associated with gut inflammation and increased permeability. • Intestinal CFTR deficiency is key to the development of liver disease in CF mice. • Restoring intestinal CFTR or modulating microbiota may improve liver disease in CF. [ABSTRACT FROM AUTHOR]

Purpose: To assess liver and spleen characteristics of a population with Gaucher disease (GD) using multiparametric MRI and MR elastography (MRE) for evaluation of diffuse liver and spleen disease, which includes liver fat fraction, liver and spleen volume and iron deposition, and liver and spleen stiffness correlated with DS3 Severity Scoring System for Gaucher disease (GD-DS3). Methods: We prospectively evaluated 41 patients with type 1 Gaucher disease using a 3.0 T MRI and MRE between January 2019 and February 2020. Clinical, laboratory, and imaging data was collected. Mann–Whitney, Kruskal–Wallis, and Spearman's correlation were applied to evaluate liver and spleen MRI and MRE, clinical and laboratory variables, and GD-DS3. ERT and SRT treatment groups were compared. Results: Hepatomegaly was seen in 15% and splenomegaly in 42% of the population. Moderate and strong and correlations were found between liver and spleen iron overload (rho = 0.537; p = 0.002); between liver and spleen volume (rho = 0.692, p < 0.001) and between liver and spleen stiffness (rho = 0.453, p = 0.006). Moderate correlations were found between liver stiffness and GD-DS3 (rho = 0.559; p < 0.001) and between splenic volume and GD-DS3 (rho = 0.524; p = 0.001). Conclusion: The prevalence of hepatosplenomegaly, liver fibrosis, and liver iron overload in treated patients with GD is low, which may be related to the beneficial effect of treatment. Liver MRE and splenic volume correlate with severity score and may be biomarkers of disease severity. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a common pathological process in the progression of several chronic liver diseases to cirrhosis and hepatocellular carcinoma. Therefore, the development of medications that can repress the progress of liver fibrosis is essential. We discovered that initially, 12β-(m-methyl-benzoyl)-11,12-dihydro oleanolic acid (12d-OA), a farnesoid X receptor (FXR) modulator, possessed potential anti-fibrotic properties. Through an in-depth study, we revealed that 12d-OA not only inhibited the expression of fibrogenic markers in the LX-2 cells and HSC-T6 cells but also exhibited significant protective effects against liver injury and liver fibrosis in bile duct ligation (BDL) rats. Further exploration of its molecular mechanism indicated that 12d-OA exerted antifibrotic activity by inhibiting the extracellular signal-regulated kinase (ERK)/stress-activated protein kinase (p38) signaling pathways. Consequently, the great effects of 12d-OA in vitro and in vivo suggest that it may be a good candidate for liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: Luseogliflozin, a sodium–glucose cotransporter 2 inhibitor, potentially exerts pleiotropic effects on the liver. However, the sufficient evidence is still lacking. We aimed to investigate the effects of luseogliflozin on hepatic steatosis, fibrosis, and cardiometabolic risk factors in diabetic patients by a pooled meta-analysis. Methods: In this pooled meta-analysis, we enrolled diabetic patients who participated in phase III clinical trials of luseogliflozin (luseogliflozin group n = 302, placebo group n = 191). The primary outcomes were changes in fatty liver index (FLI) and Hepamet fibrosis score (HFS) after 24 weeks. The secondary outcomes were changes in cardiometabolic risk factors after 24 weeks. Statistical analysis was performed using propensity scoring analysis by the inverse probability of treatment weighting method. Results: Primary outcomes: Luseogliflozin significantly decreased FLI compared to placebo after 24 weeks (adjusted coefficient − 5.423, 95%CI − 8.760 to − 2.086, P = 0.0016). There was no significant difference in changes in HFS between the two groups. However, luseogliflozin significantly decreased HFS compared to placebo in diabetic patients with ALT > 30 U/L (adjusted coefficient − 0.039, 95%CI − 0.077 to − 0.001, P = 0.0438) and with FIB-4 index > 1.3 (adjusted coefficient − 0.0453, 95%CI − 0.075 to − 0.016, P = 0.0026). Secondary outcom8es: Luseogliflozin significantly decreased HbA1c level, HOMA-IR value, BMI, and uric acids level, and increased HDL cholesterol level compared to placebo. Conclusions: This pooled meta-analysis demonstrated that 24-week treatment with luseogliflozin improved hepatic steatosis and fibrosis indexes in diabetic patients, especially those with liver injury. Furthermore, luseogliflozin improved various cardiometabolic risk factors. Thus, luseogliflozin may be useful for improving MASLD in diabetic patients. [ABSTRACT FROM AUTHOR]

Translocator protein (TSPO, 18 kDa), previously known as peripheral-type benzodiazepine receptor, is an evolutionarily conserved and tryptophan-rich 169-amino-acid protein located on the outer mitochondrial membrane. TSPO plays a crucial role in various fundamental physiological functions and cellular processes. Its expression is altered in pathological conditions, thus rendering TSPO a potential tool for diagnostic imaging and an appealing therapeutic target. The investigation of synthetic TSPO ligands as both agonists and antagonists has provided valuable insights into the regulatory mechanisms and functional properties of TSPO. Recently, accumulating evidence has highlighted the significance of TSPO in liver diseases. However, a comprehensive summary of TSPO function in the normal liver and diverse liver diseases is lacking. This review aims to provide an overview of recent advances in understanding TSPO function in both normal liver cells and various liver diseases, with a particular emphasis on its involvement in liver fibrosis and inflammation and addresses the existing knowledge gaps in the field that require further investigation. [ABSTRACT FROM AUTHOR]

Exome sequencing (ES) has identified biallelic kinesin family member 12 (KIF12) mutations as underlying neonatal cholestatic liver disease. We collected information on onset and progression of this entity. Among consecutively referred pediatric patients at our centers, diagnostic ES identified 4 patients with novel, biallelic KIF12 variants using the human GRCh38 reference sequence, as KIF12 remains incompletely annotated in the older reference sequence GRCh37. A review of these and of 21 reported patients with KIF12 variants found that presentation with elevated serum transaminase activity in the context of trivial respiratory infection, without clinical features of liver disease, was more common (n = 18) than manifest cholestatic disease progressing rapidly to liver transplantation (LT; n = 7). Onset of liver disease was at age <1 year in 15 patients; LT was more common in this group. Serum gamma‐glutamyl transpeptidase activity (GGT) was elevated in all patients, and total bilirubin was elevated in 15 patients. Liver fibrosis or cirrhosis was present in 14 of 18 patients who were biopsied. The 16 different pathogenic variants and 11 different KIF12 genotypes found were not correlated with age of onset or progression to LT. Identification of biallelic pathogenic KIF12 variants distinguishes KIF12‐related disease from other entities with elevated GGT. [ABSTRACT FROM AUTHOR]

Aim: To compare hepatic stiffness and fat fraction in patients with obesity and type 1 diabetes (T1D) with type 2 diabetes (T2D) with a similar body mass index (BMI). Methods: In this prospective cross‐sectional study, 90 participants with T1D (BMI 30.5 ± 4.5 kg/m2; diabetes duration 20.5 ± 9.8 years; HbA1c 8.2% ± 1.4%) and 69 with T2D (BMI: 30.8 ± 4.6 kg/m2; diabetes duration: 11.7 ± 7.8 years; HbA1c: 7.3% ± 1.4%) were included. Liver fat fraction and stiffness were examined by magnetic resonance imaging and elastography, respectively. Logistic regressions were used to evaluate associations with biomedical variables. Results: The mean liver stiffness score in patients with obesity and T1D was 2.2 ± 0.5 kPa, while in T2D it was 2.6 ± 0.8 kPa (P <.001). The liver fat fraction in patients with obesity and T1D was 3.7% ± 6.3%, and in T2D it was 10.6% ± 7.9% (P <.001). Metabolic dysfunction‐associated steatotic liver disease (MASLD) was present in 13.3% of patients with T1D and in 69.6% of patients with T2D, whereas fibrosis was suggested in 7.8% of patients with T1D and in 27.5% of patients with T2D. Liver stiffness was four times higher in patients with T2D compared with those with T1D (odds ratio = 5.4, 95% confidence interval: 2.1‐13.6, P <.001). Aspartate transaminase (AST), alanine transaminase, gamma‐glutamyl transferase (GGT), triglycerides and the android‐to‐gynoid ratio were associated with elevated fat fraction in both cohorts. AST and GGT were associated with elevated liver stiffness in both cohorts. Conclusions: Patients with obesity and T1D had lower liver fat and liver stiffness compared with those patients with T2D, despite similar levels of BMI, a longer duration of diabetes and worse glycaemic control. [ABSTRACT FROM AUTHOR]

Blood flow in the hepatic veins and superior vena cava (SVC) reflects right heart filling; however, their Doppler profiles are often not identical, and no studies have compared their diagnostic efficacies. We aimed to determine which venous Doppler profile is reliable for detecting elevated right atrial pressure (RAP). In 193 patients with cardiovascular diseases who underwent cardiac catheterization within 2 d of echocardiography, the hepatic vein systolic filling fraction (HV-SFF) and the ratio of the peak systolic to diastolic forward velocities of the SVC (SVC-S/D) were measured. HV-SFF < 55% and SVC-S/D < 1.9 were regarded as elevated RAP. We also calculated the fibrosis 4 index (FIB-4) as a serum liver fibrosis marker. HV-SFF and SVC-S/D were feasible in 177 (92%) and 173 (90%) patients, respectively. In the 161 patients in whom both venous Doppler waveforms could be measured, HV-SFF and SVC-S/D were inversely correlated with RAP (r = −0.350, p < 0.001; r = −0.430, p < 0.001, respectively). SVC-S/D > 1.9 showed a significantly higher diagnostic accuracy of RAP elevation compared with HV-SFF < 55% (area under the curve, 0.842 vs. 0.614, p < 0.001). Multivariate analyses showed that both FIB-4 (β = −0.211, p = 0.013) and mean RAP (β = −0.319, p < 0.001) were independent determinants of HV-SFF. In contrast, not FIB-4 but mean RAP (β = −0.471, p < 0.001) was an independent determinant of SVC-S/D. The diagnostic accuracy remained unchanged when HV-SFF < 55% was considered in conjunction with the estimated RAP based on the inferior vena cava morphology. Conversely, SVC-S/D showed an incremental diagnostic value over the estimated RAP. SVC-S/D enabled a more accurate diagnosis of RAP elevation than HV-SFF. [ABSTRACT FROM AUTHOR]

Objective(s): Liver fibrosis is a wound healing response characterized by excessive accumulation of extracellular matrix proteins. This study aimed to investigate the effects of resveratrol treatment on the TGF-β/SMAD signaling pathway and related biochemical parameters, apoptosis, and liver regeneration phenobarbital-CCl4 induced hepatic fibrosis rat model. Materials and Methods: This model was created through phenobarbital and CCl4 (0.2–0.35 ml/kg). Resveratrol (1 mg/kg/day) was administered to the fibrosis and control groups. Immunohistochemical staining was performed to evaluate αSMA, TGF-β1, and PCNA in liver tissue. The TUNEL method and Masson’s Trichome staining were used to determine apoptosis and collagen accumulation. AST, ALP, ALT, total protein, and total bilirubin levels were measured to determine biochemical status. SMAD2, SMAD3, SMAD4, and SMAD7 expression levels were measured to determine TGF-β1 related hepatic fibrosis. Results: The SMAD2, SMAD3, and SMAD4 mRNA expression levels were increased and the SMAD7 mRNA expression level was decreased in the fibrosis control group. The SMAD7 mRNA expression level was higher in the phenobarbital-CCl4 induced resveratrol treated group. Increased biochemical parameters indicating hepatic damage, increased number of apoptotic cells, and collagen accumulation surrounding the central vein were observed in the fibrosis group compared with the other groups. It was concluded that administration of resveratrol ameliorates the adverse effects of hepatic fibrosis by regulating biochemical parameters, controlling TGF-β1/SMAD signaling, enhancing tissue regeneration, and reducing apoptosis in liver cells. Conclusion: Resveratrol can be a beneficial option for the prevention of liver damage in a phenobarbital-CCl4 induced hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Objective(s): This study aimed to explore the therapeutic effect of fecal microbiota transplantation (FMT) on liver cirrhosis-induced rat models by studying changes in intestinal flora distribution and liver pathology. Materials and Methods: Cirrhosis was induced in adult male Sprague-Dawley rats using carbon tetrachloride; successful establishment of the cirrhosis model was verified using hematoxylin and eosin (HE) staining. Rats were divided into normal control, cirrhosis model+normal saline, and cirrhosis model+FMT groups. Fecal intestinal flora was analyzed using 16S rRNA high-throughput sequencing for each group. Alpha diversity, beta diversity, and functional prediction analyses were performed. Additionally, rat liver tissue was subjected to HE staining to compare the degree of fibrosis and liver damage between the groups. Results: FMT significantly improved the diversity, richness, and uniformity of the intestinal flora in rats with liver cirrhosis. Notably, post-FMT, the abundance of lactobacillaceae, bacilli, and bacteroidia increased, while the abundance of clostridia decreased. Moreover, hepatic fibrosis improved after FMT. Conclusion: The dysbiosis of intestinal flora in rats with liver cirrhosis improved after FMT. Thus, FMT can regulate intestinal flora, reduce liver inflammation, and improve hepatic fibrosis and cirrhosis. [ABSTRACT FROM AUTHOR]

Objective(s): Liver diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), pose significant global public health challenges. This study investigates the therapeutic effects of quercetin (QC), Capparis spinosa (CS), a QC and CS combination, and Saroglitazar (SARO) on NASH in a Wistar rat model. Materials and Methods: NASH was induced by a 42-day high-fat diet regimen in male Wistar rats. Post-induction, rats were divided into five groups receiving SARO, QC, CS, and CS+QC combination. We monitored changes in liver and body weights and evaluated the expression of genes associated with fatty acid biosynthesis (e.g., ACC and FAS), β-oxidation (e.g., CPT1, PPAR α), inflammation (e.g., TNF-α and IL-6), and fibrosis (e.g., TGF-β and COL1A), as well as protein expression levels of p-Smad2/3 and p-Smad3. Results: Treatment with QC+CS significantly decreased liver weight, body mass gain, and liver triglyceride (TG) compared to other treatments. The QC and CS combined therapy also resulted in a greater normalization of hepatic enzymatic activities, including decreases in ALT and AST levels, coupled with improvements in lipid profile indicated by decreased LDL-C and increased HDL-C concentrations, as compared to SARO and QC alone. Furthermore, this combined treatment significantly down-regulated the expression of TGF-β, TNF-α, IL-6 genes, and Smad2/3 and Smad3 protein levels. Conclusion: Our study demonstrates that an interactive effect between QC and CS can effectively reduce liver fibrosis and steatosis by inhibiting the TGF-β/Smad3 signaling pathway in a diet-induced model of nonalcoholic steatohepatitis and fibrosis in rats. [ABSTRACT FROM AUTHOR]

Purpose: The well-established relationship between obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) is a key etiological factor in the development of liver cirrhosis. Bariatric surgery is an effective treatment for weight loss in patients with moderate-to-severe obesity, also playing a role in controlling MASLD. However, surgical safety in patients with advanced fibrosis remains to be established. This study aimed to evaluate the safety and repercussions of bariatric surgery according to fibrosis stage. Materials and Methods: Patients undergoing bariatric surgery who had an intraoperative liver biopsy were retrospectively evaluated. Preoperative and postoperative data were collected from medical records, and results were stratified according to fibrosis stage into early fibrosis (no fibrosis or stages 1 and 2) and advanced fibrosis (stages 3 and 4). Results: The study included 1185 patients: 1129 with early fibrosis and 56 with advanced fibrosis. The advanced fibrosis group had higher percentage of men (35.7% vs 21.6%, p = 0.014) and of people with diabetes (42.9% vs 16.5%, p < 0.001) and hypertension (57.1% vs 41.4%, p = 0.012). Patients with advanced fibrosis also required longer hospitalizations (4.64 vs 4.06 days, p < 0.001) and were more frequently admitted to the intensive care unit (7.1% vs 2.9%, p = 0.038). The groups did not differ significantly in other outcomes. There were no deaths in either group. Conclusion: Bariatric surgery proved to be safe, with similar complication rates in patients with advanced fibrosis and in those with early fibrosis. [ABSTRACT FROM AUTHOR]

Background: Metabolic-associated fatty liver disease and liver fibrosis are intimately linked to insulin resistance, type 2 diabetes, obesity, and metabolic syndrome. Transient elastography (TE) and point shear wave elastography (pSWE) were used to measure liver stiffness in patients who met the ultrasound criteria for steatotic liver diseases (SLD). This study compared two methods for estimating liver stiffness in patients with SLD, which in turn correlated with liver fibrosis. Method: Ultrasound B-mode imaging was used to identify SLD. In total, 250 MAFLD patients were recruited. Patient characteristics, laboratory investigations, and liver stiffness measurements using TE and pSWE were assessed on the same day. Results: In the study, 56.0% of the patients were male, with a mean age of 41.5 ± 10.7 years. The correlation between TE and pSWE was significant (Spearman's r = 0.867*, p < 0.001). The Bland-Altman Plot analysis confirmed this, with 97.5% of variations in LSM falling within 95% agreement ranges. Cohen's κ was used to assess the agreement between TE and pSWE fibrosis stages, showing almost perfect agreement (83.5% kappa agreement) and a strong association between pSWE and TE in the assessment fibrosis stages. Conclusion: In patients with MAFLD, TE, and SWE are reliable methods for measuring liver stiffness and can be used as non-invasive screening tools for the assessment of fibrosis in SLD. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethods and findingsConclusionAbbreviationsHepatitis C virus (HCV) is a major cause of chronic liver disease, in which liver stiffness increases. Liver stiffness measurements (LSM) are therefore essential in diagnosing liver diseases and predicting disease development. The study objective was to perform a comprehensive prospective assessment of the liver before, after and 4 years after treatment for HCV, including an assessment of the long-term outcome of fibrosis, steatosis and inflammation.Patients eligible for HCV treatment were included prospectively in 2018 (n = 47). Liver stiffness was measured using transient elastography and 2D shear-wave elastography (SWE). Blood tests, B-mode ultrasound (US) and SWE, were performed before, after (end of treatment [EOT]), 3 months after (EOT3) and 4 years after treatment (4Y). At the final visit, we added attenuation imaging and shear-wave dispersion slope (SWDS) measurements to assess steatosis and inflammation. Three months after treatment, the sustained virologic response rate was 93%. The median liver stiffness for baseline, EOT, EOT3 and 4Y was 8.1, 5.9, 5.6 and 6.3 kPa, respectively. There was a significant reduction in liver stiffness from baseline to EOT, and from EOT to EOT3. After 4 years, the mean attenuation coefficient (AC) was 0.58 dB/cm/MHz, and the mean SWDS value was 14.3 (m/s)/kHz.The treatment for HCV was highly effective. Measurements of liver stiffness decreased significantly after treatment and remained low after 4 years. AC measurements indicated low levels of liver steatosis. Shear-wave dispersion values indicated inflammation of the liver, but the clinical implication is undetermined and should be explored in larger studies.Clinicaltrials.gov: NCT03434470AC: attenuation coefficient; APRI: aspartate aminotransferase to platelet ratio index; ATI: attenuation imaging; cACLD: compensated advanced chronic liver disease; CAP: controlled attenuation parameter; FIB-4: Fibrosis-4 Index for liver fibrosis; HCC: hepatocellular carcinoma; LSM: liver stiffness measurement; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; SWDS: shear-wave dispersion slope; SWE: shear-wave elastography; US: ultrasound [ABSTRACT FROM AUTHOR]

Salvianolic acid B (SalB), among the most abundant bioactive polyphenolic compounds found in Salvia miltiorrhiza Bge., exerts therapeutic and protective effects against various diseases. Although some summaries of the activities of SalB exist, there is lack of a scientometric and in-depth review regarding disease therapy. In this review, scientometrics was employed to analyze the number of articles, publication trends, countries, institutions, keywords, and highly cited papers pertaining to SalB research. The scientometric findings showed that SalB exerts excellent protective effects on the heart, lungs, liver, bones, and brain, along with significant therapeutic effects against atherosclerosis (AS), Alzheimer’s disease (AD), liver fibrosis, diabetes, heart/brain ischemia, and osteoporosis, by regulating signaling pathways and acting on specific molecular targets. Moreover, this review delves into in-depth insights and perspectives, such as the utilization of SalB in combination with other drugs, the validation of molecular mechanisms and targets, and the research and development of novel drug carriers and dosage forms. In conclusion, this review aimed to offer a comprehensive scientometric analysis and in-depth appraisal of SalB research, encompassing both present achievements and future prospects, thereby providing a valuable resource for the clinical application and therapeutic exploitation of SalB. [ABSTRACT FROM AUTHOR]

Background and Aim Method Results Conclusion We assessed the effect of hepatitis B surface antigen (HBsAg) seroclearance (HBsAg‐loss) on liver fibrosis regression in patients with chronic hepatitis B (CHB) infection.CHB patients with recent documented HBsAg‐loss were age‐ and gender‐matched with treatment‐naïve HBeAg‐negative CHB infection. Paired assessment with transient elastography and enhanced liver fibrosis (ELF) measurements were performed and repeated at 3 years. Fibrosis regression was arbitrarily defined as decrease in ≥ 1 fibrosis stage by ELF, or combining with reduction > 30% in liver stiffness.A total of 142 HBsAg‐loss and 142 CHB subjects were recruited (median age 58.1 years, 51.4% male). A total of 1.8% (1.4% HBsAg‐loss vs 2.1% CHB) achieved combined endpoint of fibrosis regression at 3 years. When ELF‐only definition of fibrosis regression was used, 14.5% HBsAg‐loss and 16.9% CHB subjects achieved this endpoint, which was significantly associated with baseline ELF (hazard ratio (HR) 1.827, 95% confidence interval (CI) 1.085–3.075) and time since HBsAg‐loss (HR 2.688, 95% CI 1.257–5.748). While increasing time since HBsAg‐loss increased the proportion of ELF‐defined fibrosis regression, increasing age was also associated with significant fibrosis. Age of achieving HBsAg‐loss (ageSC) was independently associated with high baseline ELF values. Up to 52.3% and 63.8% subjects with ageSC > 50 had advanced fibrosis/cirrhosis at baseline and 3 years, respectively, compared with 5.9% and 20.6% in subjects with ageSC < 50.Fibrosis regression occurred in a minority of subjects achieving HBsAg‐loss, which was not significantly different compared with subjects with persistent overt CHB. Subjects after achieving HBsAg‐loss, especially among those with ageSC > 50, should receive ongoing surveillance for liver‐related complications. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion This study aimed at ascertaining the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with donafenib versus HAIC alone in the treatment of unresectable hepatocellular carcinoma (HCC).Seventy HCC patients were enrolled for our study, and they were randomized by simple randomization using computer‐generated random numbers into two groups: control group and observation group. Regular follow‐up reviews were conducted to assess the efficacy of treatments. The levels of apoptotic factors, the levels of hepatic fibrosis indices, the levels of serum tumor vascular factors and tumor markers, and the occurrence of adverse reactions in the two groups were recorded and compared.Disease control rate, objective response rate, and progression‐free survival (PFS) of patients in the observation group were higher in contrast to the control group. After 12 weeks of treatment, lower mRNA expression of c‐mesenchymal‐epithelial transition factor, telomerase, and Fas Ligand and higher mRNA expression of Fas and Caspase‐3 were observed in HCC tissues of the observation group versus the control group (p < 0.05); lower detection values of serum laminin, hyaluronic acid, collage type IV, vascular endothelial growth factor receptor 2, and alpha‐fetal protein (AFP) were noted in HCC patients of the observation group in comparison to the control group (p < 0.05); there was no difference in the incidence of adverse reactions between the two groups.Donafenib combined with HAIC in the treatment of unresectable HCC patients can notably reduce serum AFP levels, improve hepatic fibrosis, enhance short‐term efficacy, prolong PFS, and have a favorable safety profile. [ABSTRACT FROM AUTHOR]

The prevalence of Metabolic-associated fatty liver disease (MAFLD) has been steadily increasing worldwide, paralleling the global epidemic of obesity and diabetes. It is estimated that approximately one-quarter of the global population is affected by MAFLD. Despite its high prevalence, MAFLD often goes undiagnosed due to the lack of specific symptoms in its early stages. However, as the disease progresses, it can lead to more severe liver-related complications such as fibrosis, cirrhosis, and hepatocellular carcinoma. Therefore, we aimed to investigate the expression levels of the nucleotide-binding oligomerization domain, leucine-rich repeat (LRR)—containing proteins (NLR) family pyrin domain-containing protein 3 [NLRP3] inflammasome pathway components, NLRP3 and interleukin 1β (IL-1β) genes in patients with MAFLD with various degrees of steatosis and fibrosis. Participants were classified into two equal groups; MAFLD group: consisted of 120 patients with different degrees of hepatic fibrosis and steatosis based on fibro scan results. The non-MAFLD group was comprised of 107 participants. Molecular analysis of pyrin domain-containing protein 3 and IL-1β relative gene expressions was performed in the blood of all participants, using Real-time quantitative polymerase chain reaction (RT-qPCR). Patients with post-MAFLD hepatic fibrosis had significantly higher relative gene expression levels of IL-1β and NLRP3; with IL-1β > 1.1 had AUC of 0.919, sensitivity of 88.33, specificity of 96.26, PPV of 96.4, and NPV of 88 and 92.3 accuracy (p value < 0.001). NLRP3 > 1.33 had a sensitivity of 97.5, specificity of 99.07, PPV of 99.2, NPV of 97.2, and 98.3 accuracy with an AUC of 0.991 (p value < 0.001) as predictors of post-MAFLD hepatic fibrosis.. A significant increase in the mean relative gene expression levels of both IL-1β and NLRP3 found in patients with early fibrosis (F0-F1-2); 31.97 ± 11.8 and 6.76 ± 2.18, respectively; compared with patients with advanced hepatic fibrosis stages (F2-F3); 2.62 ± 3.71 and 4.27 ± 2.99 (p < 0.001 each). The present study provides novel evidence for the possible involvement of IL-1β and NLRP3 inflammasome in metabolic-associated fatty liver disease pathogenesis and could be valid markers for the early detection of post-MAFLD hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Background: There is a contradiction in the use of microbiota-therapies, including probiotics, prebiotics, and synbiotics, to improve the condition of patients with nonalcoholic fatty liver disease (NAFLD). The aim of this review was to evaluate the effect of microbiota-therapy on liver injury, inflammation, and lipid levels in individuals with NAFLD. Methods: Using Pubmed, Embase, Cochrane Library, and Web of Science databases were searched for articles on the use of prebiotic, probiotic, or synbiotic for the treatment of patients with NAFLD up to March 2024. Results: Thirty-four studies involving 12,682 individuals were included. Meta-analysis indicated that probiotic, prebiotic, and synbiotic supplementation significantly improved liver injury (hepatic fibrosis, SMD = -0.31; 95% CI: -0.53, -0.09; aspartate aminotransferase, SMD = -0.35; 95% CI: -0.55, -0.15; alanine aminotransferase, SMD = -0.48; 95% CI: -0.71, -0.25; alkaline phosphatase, SMD = -0.81; 95% CI: -1.55, -0.08), lipid profiles (triglycerides, SMD = -0.22; 95% CI: -0.43, -0.02), and inflammatory factors (high-density lipoprotein, SMD = -0.47; 95% CI: -0.88, -0.06; tumour necrosis factor alpha, SMD = -0.86 95% CI: -1.56, -0.56). Conclusion: Overall, supplementation with probiotic, prebiotic, or synbiotic had a positive effect on reducing liver enzymes, lipid profiles, and inflammatory cytokines in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Identifying new molecular therapies targeted at the severe hepatic fibrosis associated with the granulomatous immune response to Schistosoma mansoni infection is essential to reduce fibrosis-related morbidity/mortality in schistosomiasis. In vitro cell activation studies suggested the lipid molecule prostaglandin D2 (PGD2) as a potential pro-fibrotic candidate in schistosomal context, although corroboratory in vivo evidence is still lacking. Here, to investigate the role of PGD2 and its cognate receptor DP2 in vivo, impairment of PGD2 synthesis by HQL-79 (an inhibitor of the H-PGD synthase) or DP2 receptor inhibition by CAY10471 (a selective DP2 antagonist) were used against the fibrotic response of hepatic eosinophilic granulomas of S. mansoni infection in mice. Although studies have postulated PGD2 as a fibrogenic molecule, HQL-79 and CAY10471 amplified, rather than attenuated, the fibrotic response within schistosome hepatic granulomas. Both pharmacological strategies increased hepatic deposition of collagen fibers–an unexpected outcome accompanied by further elevation of hepatic levels of the pro-fibrotic cytokines TGF-β and IL-13 in infected animals. In contrast, infection-induced enhanced LTC4 synthesis in the schistosomal liver was reduced after HQL-79 and CAY10471 treatments, and therefore, inversely correlated with collagen production in granulomatous livers. Like PGD2-directed maneuvers, antagonism of cysteinyl leukotriene receptors CysLT1 by MK571 also promoted enhancement of TGF-β and IL-13, indicating a key down-regulatory role for endogenous LTC4 in schistosomiasis-induced liver fibrosis. An ample body of data supports the role of S. mansoni-driven DP2-mediated activation of eosinophils as the source of LTC4 during infection, including: (i) HQL-79 and CAY10471 impaired systemic eosinophilia, drastically decreasing eosinophils within peritoneum and hepatic granulomas of infected animals in parallel to a reduction in cysteinyl leukotrienes levels; (ii) peritoneal eosinophils were identified as the only cells producing LTC4in PGD2-mediated S. mansoni-induced infection; (iii) the magnitude of hepatic granulomatous eosinophilia positively correlates with S. mansoni-elicited hepatic content of cysteinyl leukotrienes, and (iv) isolated eosinophils from S. mansoni-induced hepatic granuloma synthesize LTC4in vitro in a PGD2/DP2 dependent manner. So, our findings uncover that granulomatous stellate cells-derived PGD2 by activating DP2 receptors on eosinophils does stimulate production of anti-fibrogenic cysLTs, which endogenously down-regulates the hepatic fibrogenic process of S. mansoni granulomatous reaction–an in vivo protective function which demands caution in the future therapeutic attempts in targeting PGD2/DP2 in schistosomiasis. Author summary: Accumulation of scar tissue (fibrosis) in the liver is the main cause of health problems associated with schistosomiasis even after the parasite is eliminated by treatment with anthelmintics. Previous experiments with isolated cells in culture have identified a potential role for a lipid mediator, PGD2, in promoting liver fibrosis leading to suggestions that PGD2 inhibition may be beneficial for the people infected with Schistosoma parasite. However, there was no direct evidence in an infection model to support these claims. Here, we described the effect of inhibiting the production or action of PGD2 in a mouse model of schistosomiasis. We identified the cell target and mechanism of action of PGD2's participation in schistosomiasis. However, our data indicates that PGD2 protects the liver from fibrosis. Thus, inhibition of PGD2 action in patients infected with the Schistosoma parasite may aggravate the condition and promote faster liver failure and should not be pursued as a treatment option. [ABSTRACT FROM AUTHOR]

Background: Parkinson disease (PD) is one of the disabling neurological disorders. The etiology of Parkinson disease is still unknown. Hepatitis C virus is one of the neurotropic viruses which is incriminated in the pathogenesis of Parkinson disease. Hepatitis C virus might affect the dopaminergic neurons, affecting the advancement of PD. Methods: This study is observational, cross-sectional study done on 2 phases: one phase on PD patients without history of HCV and another phase on HCV patients with no history of PD. 104 PD patient were tested for HCV antibodies and 40 HCV patients with various grades of liver fibrosis were assessed for early pre-motor symptoms of parkinsonism. Results: Among patients with parkinsonism, HCV Abs testing was negative in all the studied patients. On the other hand, chronic HCV group included 40 patients, 27.5% were cirrhotic (11/40). Child C patients showed significantly higher percentages of non-motor parkinsonian symptoms, and regarding the HCV group, the majority (85%) of the patients show cognitive impairment, (27.5%) were at stage 1 of anxious mood, while half (50%) of the patients were at stage 1 of fatigue as evaluated by UPDRS Score. Cirrhosis was a significant factor for having non-motor (early) parkinsonism. Conclusion: Here we show that advanced cirrhosis is associated with a variety of neurological symptoms including parkinsonian, which needs awareness for better preventive and therapeutic measures for early treatment of hepatitis avoiding the occurrence of cirrhosis, which can lead to parkinsonism. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a chronic pathological condition lacking specific clinical treatments. Stem cells, with notable potential in regenerative medicine, offer promise in treating liver fibrosis. However, stem cell therapy is hindered by potential immunological rejection, carcinogenesis risk, efficacy variation, and high cost. Stem cell secretome‐based cell‐free therapy offers potential solutions to address these challenges, but it is limited by low delivery efficiency and rapid clearance. Herein, an innovative approach for in situ implantation of smart microneedle (MN) arrays enabling precisely controlled delivery of multiple therapeutic agents directly into fibrotic liver tissues is developed. By integrating cell‐free and platinum‐based nanocatalytic combination therapy, the MN arrays can deactivate hepatic stellate cells. Moreover, they promote excessive extracellular matrix degradation by more than 75%, approaching normal levels. Additionally, the smart MN arrays can provide hepatocyte protection while reducing inflammation levels by ≈70–90%. They can also exhibit remarkable capability in scavenging almost 100% of reactive oxygen species and alleviating hypoxia. Ultimately, this treatment strategy can effectively restrain fibrosis progression. The comprehensive in vitro and in vivo experiments, supplemented by proteome and transcriptome analyses, substantiate the effectiveness of the approach in treating liver fibrosis, holding immense promise for clinical applications. [ABSTRACT FROM AUTHOR]

Because hepatic stellate cells (HSCs) play a major role in fibrosis, we focused on HSCs as a potential target for the treatment of liver fibrosis. In this study, we attempted to identify drug candidates to inactivate HSCs and found that several proteasome inhibitors (PIs) reduced HSC viability. Our data showed that a second-generation PI, carfilzomib (CZM), suppressed the expression of fibrotic markers in primary murine HSCs at low concentrations of 5 or 10 nM. Since CZM was not toxic to HSCs up to a concentration of 12.5 nM, we examined its antifibrotic effects further. CZM achieved a clear reduction in liver fibrosis in the carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis without worsening of liver injury. Mechanistically, RNA sequence analysis of primary HSCs revealed that CZM inhibits mitosis in HSCs. In the CCl4-injured liver, amphiregulin, which is known to activate mitogenic signaling pathways and fibrogenic activity and is upregulated in murine and human metabolic dysfunction-associated steatohepatitis (MASH), was downregulated by CZM administration, leading to inhibition of mitosis in HSCs. Thus, CZM and next-generation PIs in development could be potential therapeutic agents for the treatment of liver fibrosis via inactivation of HSCs without liver injury. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionSkin flap transplantation is used to effectively reconstruct defects of the hand and foot skin and soft tissues. We here investigated the effect of the PF127/bleomycin (BLM) hydrogel on the extracellular matrix (ECM) remodeling of skin flaps and the underlying mechanism, thereby providing a new reference point for personalized flap modification and overcoming abrasion resistance- and stability-associated difficulties.The appropriate PF127/BLM concentration was selected based on the gelation time and drug release curve. Migration assays, scratch assays, and live/dead staining were conducted to verify the effect of PF127/BLM on human skin fibroblasts (HSFs). The effects of PF127/BLM on the ECM were assessed through hematoxylin and eosin and Masson staining. Additionally, we examined the expression of ECM remodeling-related genes and proteins involved in their associated signaling pathway. Finally, the effects of PF127/BLM on organ fibrosis and toxicity to liver and kidney functions were assessed in mice.A 25% PF127/BLM hydrogel was selected as the study concentration. PF127/BLM augmented HSF chemotaxis and proliferation. Furthermore, PF127/BLM promoted subcutaneous ECM remodeling and fibrosis, increased the flap dermis thickness, and reduced the toxic side effects of BLM on liver/lung fibrosis and liver/kidney function. Additional studies confirmed that the PF127/BLM-mediated regulation of ECM remodeling in skin flaps was associated with TGFβ-Col signaling pathway activation.The PF127/BLM hydrogel promoted subcutaneous ECM remodeling and fibrosis, which aided the construction of personalized flaps through the TGFβ-Col signaling pathway, with decreased hepatic, pulmonary, and renal toxicities. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions To examine the dynamic change in hepatic steatosis status during repeated assessments over time, and its potential impact on the risk of developing cardiovascular disease (CVD).We assessed trajectories of hepatic steatosis and other metabolic disorders in 3134 middle‐aged adults undergoing longitudinal assessment of ultrasonography during a pre‐baseline period (1993–2009) in a population‐based cohort study of liver health. Subsequently, we determined the association of hepatic steatosis trajectories with the incidence of CVD among 2185 CVD‐free individuals, followed until 2021. Metabolic risk factors and cardiovascular events (including coronary heart disease and stroke) were determined through medical examination and linkage with nationwide health databases.We identified three discrete trajectories of hepatic steatosis according to changing pattern over time through group‐based trajectory modeling: “stable, non‐steatosis” (n = 1298), “intermittent” (n = 921), and “persistent steatosis” (n = 915). During the pre‐baseline period, hepatic steatosis trajectories were associated with trajectories of developing diabetes and hypertension, and persistent steatosis (vs. other trajectories) was associated with higher risks and rapidly progressive disease patterns. At a median 13.6 years of follow‐up, 629 CVD events occurred. A persistent (vs. non‐steatosis: HR 1.44, 95% CI 1.17–1.76), but not intermittent, steatosis pattern predicted the future risk of CVD, after adjustment for age, sex, smoking, and obesity. This association was independent of genetic background, and remained after accounting for pre‐baseline body‐mass index, other cardiometabolic risk factors, Framingham risk score, medications, and hepatic fibrosis score.The persistence of hepatic steatosis is associated with trajectories of metabolic disorder development and increased risk of CVD. These data have important implications for practice and further research. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome characterized by excessive fat deposition in hepatocytes and a major cause of end-stage liver disease. Autophagy is a metabolic pathway responsible for degrading cytoplasmic products and damaged organelles, playing a pivotal role in maintaining the homeostasis and functionality of hepatocytes. Recent studies have shown that pharmacological intervention to activate or restore autophagy provides benefits for liver function recovery by promoting the clearance of lipid droplets (LDs) in hepatocytes, decreasing the production of pro-inflammatory factors, and inhibiting activated hepatic stellate cells (HSCs), thus improving liver fibrosis and slowing down the progression of NAFLD. This article summarizes the physiological process of autophagy, elucidates the close relationship between NAFLD and autophagy, and discusses the effects of drugs on autophagy and signaling pathways from the perspectives of hepatocytes, kupffer cells (KCs), and HSCs to provide assistance in the clinical management of NAFLD. [ABSTRACT FROM AUTHOR]

Background: There has been controversy and uncertainty regarding the causal relationship between type 1 diabetes, its consequences, liver fibrosis, and cirrhosis. In order to determine the causal relationship, we conducted a Mendelian randomization study (MR). Methods: For the first time, we subjected multiple diabetes data to analyze its relationship with the progression of liver fibrosis. Once the instrumental variables had been extracted, we assessed them employing Cochran's Q multi-analysis, inverse variance weighted, MR-Egger, MR-PRESSO, weighted mode, and weighted median. Results: Genetically predicted type 1 diabetes (OR = 1.13, 95% CI: 1.04-1.23, **P = 3.42 x 10-3), type 1 diabetes without complications (OR = 1.12, 95% CI: 1.03-1.23, *P = 1.26 x 10-2), type 1 diabetes with coma (OR = 1.09, 95% CI: 1-1.18, *P = 4.74 x 10-2), type 1 diabetes with ketoacidosis (OR = 1.07, 95% CI: 1.01-1.13, *P=1.3 x 10-2), type 1 diabetes with neurological complications (OR = 1.18, 95% CI: 1.11-1.26, ***P = 4.05 x 10-7), type 1 diabetes with ophthalmic complications (OR = 1.16, 95% CI: 1.05-1.28, **P = 3.06 x 10-3), type 1 diabetes with renal complications (OR = 1.07, 95% CI: 1-1.13, *P = 3.45 x 10-2), type 1 diabetes with other specified/multiple/unspecified complications (OR = 1.12, 95% CI: 1.02-1.23, *P = 1.41 x 10-2) were all associated with an increased risk of liver fibrosis progression. Conclusions: According to our MR investigation, type 1 diabetes and both its acute and chronic implications may increase the likelihood that liver fibrosis could continue to develop. Additionally, type 1 diabetes with neurological and ocular problems is more likely to accelerate the development of liver fibrosis and inflammation, which offers new insights for genetic investigations. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Conclusions Recently, a new entity was introduced, MetALD, which includes patients with metabolic dysfunction‐associated steatotic liver disease (MASLD), who consume moderate amounts of alcohol. However, little is known regarding the metabolic and clinical characteristics of these patients.Data from the National Health and Nutrition Examination Surveys 2017–2020 was used. Participants without valid transient elastography (TE) measurements, incomplete alcohol consumption report, or with alternative etiologies of liver steatosis were excluded.A total of 6901 patients were included in the study, of which 106 (1.5%) had MetALD. Overall, MetALD patients showed a metabolic profile that was more similar to patients with alcohol related liver disease (ALD) than MASLD. Specifically, while patients with MetALD showed values in‐between MASLD and ALD for body mass index (BMI), aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyltransferase (GGT) and haemoglobin A1c, they had similar high‐density lipoprotein cholesterol (HDL‐C), blood pressure, prevalence of diabetes and insulin resistance to ALD patients. Increasing alcohol consumption was associated with lower insulin resistance and A1c and higher triglycerides, HDL‐C and blood pressure. Moreover, while AST, ALT and GGT increased with alcohol consumption, this did not translate into worse hepatic steatosis or liver fibrosis by TE.MetALD patients share some characteristics with MASLD, but they resemble ALD patients more, especially after adjusting for BMI. Alcohol consumption produces a dissociation between insulin resistance and some cardiometabolic risk factors (blood pressure and HDL‐C), which may make the current classification of patients challenging. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunctionassociated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits. [ABSTRACT FROM AUTHOR]

Background/Objectives: The health burden of metabolic dysfunction-associated fatty liver disease (MASLD) has been increasing lately. Cardiovascular disease (CVD) is the main cause of death in MASLD patients; therefore, the treatments for MASLD should improve both CV risk factors such as obesity, diabetes, and dyslipidemia, in addition to an improvement in liver function. The evidence on the long-term effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on the progression of MASLD in Asian populations is very limited. Methods: The retrospective longitudinal study was performed by using the medical records at our institute. We picked up patients with type 2 diabetes who had taken SGLT2is for at least 3 years or longer between 1 April 2014 and 31 March 2018. We collected the data on metabolic parameters, including laboratory data and anthropometric parameters, and compared the data before and after the initiation of SGLT2is treatment. Results: During the observation period, 324 patients had taken SGLT2is for 3 years. Three-year SGLT2is treatment significantly reduced body weight, hemoglobin A1c, low-density lipoprotein cholesterol, triglyceride, and non-high-density lipoprotein cholesterol (non-HDL-C). Such favorable changes in serum lipids were remarkable in patients with statins. Furthermore, this treatment significantly improved liver function and the markers for hepatic steatosis and hepatic fibrosis. Conclusions: Considering that the development of CVD determines the prognosis of MASLD patients, long-term SGLT2is treatment may be an ideal therapy for MASLD patients. [ABSTRACT FROM AUTHOR]

Liver fibrosis progressing to cirrhosis is a major risk factor for liver cancer, impacting surgical treatment and survival. Our study focuses on the role of extracellular nicotinamide adenine dinucleotide (eNAD+) in liver fibrosis, analyzing liver disease patients undergoing surgery. Additionally, we explore NAD+'s therapeutic potential in a mouse model of extended liver resection and in vitro using 3D hepatocyte spheroids. eNAD+ correlated with aspartate transaminase (AST) and bilirubin after liver resection (AST: r = 0.2828, p = 0.0087; Bilirubin: r = 0.2584, p = 0.0176). Concordantly, post-hepatectomy liver failure (PHLF) was associated with higher eNAD+ peaks (n = 10; p = 0.0063). Post-operative eNAD+ levels decreased significantly (p < 0.05), but in advanced stages of liver fibrosis or cirrhosis, this decline not only diminished but actually showed a trend towards an increase. The expression of NAD+ biosynthesis rate-limiting enzymes, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3), were upregulated significantly in the liver tissue of patients with higher liver fibrosis stages (p < 0.0001). Finally, the administration of NAD+ in a 3D hepatocyte spheroid model rescued hepatocytes from TNFalpha-induced cell death and improved viability (p < 0.0001). In a mouse model of extended liver resection, NAD+ treatment significantly improved survival (p = 0.0158) and liver regeneration (p = 0.0186). Our findings reveal that eNAD+ was upregulated in PHLF, and rate-limiting enzymes of NAD+ biosynthesis demonstrated higher expressions under liver fibrosis. Further, eNAD+ administration improved survival after extended liver resection in mice and enhanced hepatocyte viability in vitro. These insights may offer a potential target for future therapies. An analysis on liver disease patients suggests that extracellular Nicotinamide adenine dinucleotide (eNAD + ) correlates with liver fibrosis and post-hepatectomy liver failure, with NAD+ administration improving survival and liver regeneration in mice and hepatocyte viability in vitro. [ABSTRACT FROM AUTHOR]

Background: Artemisinin (ART) analogs, such as dihydroartemisinin, arteether, artemether, and artesunate, all featuring an endoperoxide bridge, have demonstrated efficacy against schistosomiasis. Artemisitene (ATT), which contains an additional α, β-unsaturated carbonyl structure, has shown enhanced biological activities. This study aims to evaluate the anti-schistosomaiasis japonica activity of ATT and compare it with ART. Methods: We assessed liver inflammation and fibrosis in mice using hematoxylin and eosin staining and Sirius red staining, respectively. RNA sequencing analyzed transcriptomics in female and male Schistosoma japonicum (S. japonicum) adult worms and mice livers, with cytokine profiling and flow cytometry to study immune responses under ART or ATT treatment. Results: ATT exhibits a marked reduction in female S. japonicum adult worms and egg numbers, damaging the adult worms' surface. It also influences the transcription of genes related to cellular anatomical structures. Notably, ATT treatment resulted in significant reductions in liver granuloma size and collagen area, alongside lowering serum levels of glutamic pyruvic and glutamic oxaloacetic transaminase more effectively than ART. Both ART and ATT markedly decreased neutrophil frequency in the liver and elevated eosinophil counts. However, only ATT treatment significantly reduced the M1/M2 and Th1/Th2 indices, indicating a pronounced shift in immune response profiles. ATT-affected host immunity correlated with the extent of liver fibrosis and the count of single males more strongly than ART. Conclusion: ATT, as a novel preventive strategy for schistosomiasis japonica in mice, significantly outperforms ART. [ABSTRACT FROM AUTHOR]

The combination of lineage tracing and immunohistochemistry has helped to identify subpopulations and fate of hepatic stellate cells (HSC) in murine liver. HSC are sinusoidal pericytes that act as myofibroblast precursors after liver injury. Single cell RNA sequencing approaches have recently helped to differentiate central and portal HSC. A specific Cre line to lineage trace portal HSC has not yet been described. We used three Cre lines (Lrat-Cre, PDGFRβ-CreERT2 and SMMHC-CreERT2) known to label mesenchymal cells including HSC in combination with a tdTomato-expressing reporter. All three Cre lines labeled populations of HSC as well as smooth muscle cells (SMC). Using the SMMHC-CreERT2, we identified a subtype of HSC in the periportal area of the hepatic lobule (termed zone 1-HSC). We lineage traced tdTomato-expressing zone 1-HSC over 1 year, described fibrotic behavior in two fibrosis models and investigated their possible role during fibrosis. This HSC subtype resides in zone 1 under healthy conditions; however, zonation is disrupted in preclinical models of liver fibrosis (CCl4 and MASH). Zone 1-HSC do not transform into αSMA-expressing myofibroblasts. Rather, they participate in sinusoidal capillarization. We describe a novel subtype of HSC restricted to zone 1 under physiological conditions and its possible function after liver injury. In contrast to the accepted notion, this HSC subtype does not transform into αSMA-positive myofibroblasts; rather, zone 1-HSC adopt properties of capillary pericytes, thereby participating in sinusoidal capillarization. [ABSTRACT FROM AUTHOR]