AimsThis exploratory study aimed to identify the effects of SIRT1 polymorphisms on the serum lipidomic profile and pathological characteristics in metabolic dysfunction-associated steatotic liver disease (MASLD).MaterialsChinese Han patients with biopsy-proven MASLD were genotyped for the single nucleotide polymorphisms (SNPs) in SIRT1. Lipidomics based on untargeted ultra-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS) was applied to map the SIRT1-driven serum lipid signature, followed by correlation analyses linking these lipid traits to hepatic steatosis, ballooning, lobular inflammation, and fibrosis. Integrative pathological scoring finally explored how SIRT1 variants that remodel circulating lipids may be associated with MASLD-specific histological change.ResultsSIRT1 SNPs (rs3740053, rs2394443, rs2236318, rs7896005, rs2273773, rs2394445, and rs2394446) demonstrated extensive association with serum lipidomics of MASLD patients. SIRT1 rs2236318, rs7896005, and rs2394445, affecting 2, 7, and 7 serum triacylglycerols (TAGs) respectively, dominated the SIRT1 SNP-lipidomics association. Quantitative analysis revealed significantly elevated TAGs levels (48:0, 50:0, 50:1, 52:0, 52:1, 52:2, and 54:1), the most abundant species, in MASLD patients with rs2394445 A/A genotype compared with A/T+T/T. These elevated rs2394445-dependent TAG levels were associated with high-grade hepatic steatosis (rho: 0.367 to 0.540, p < 0.033–0.001) rather than ballooning, lobular inflammation, or fibrosis. The significant correlation of rs2394445 A/A genotype with severe steatosis suggested a potential pathological link through TAG profile modulation. In contrast, rs2394445 showed a limited effect on total circulating lipids and obesity indices (BMI, WHtR).ConclusionThe A/A genotype at SIRT1 rs2394445 is associated with elevated serum TAGs containing saturated or monounsaturated fatty acids, which are linked to high-grade hepatic steatosis in MASLD independently of obesity.

This study aimed to construct and validate a nomogram to predict the long-term incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) and metabolic dysfunction (MD) receiving antiviral therapy. 809 individuals with hepatitis B combined with metabolic dysfunction who received antiviral therapy between 2009 and 2023 were randomly assigned to the training and validation cohorts in a 6:4 ratio using simple randomization performed with the sample function in R software (version 4.3.2). Independent risk factors for HCC were identified by Cox regression analysis, and a nomogram was subsequently constructed. The model’s performance was evaluated using calibration curves, decision curve analysis (DCA), and the area under the receiver operating characteristic curve (AUC). Independent predictors of HCC development identified by multivariate Cox regression included lymphocyte count, the Triglyceride-Glucose index, and the modified PAGE-B score. These were incorporated into a nomogram with a total score range of 0 to 200 for risk prediction. The nomogram yielded a 3-year AUC of 0.828, numerically higher than established scores; however, DeLong tests confirmed no statistically significant superiority. Using the nomogram for risk stratification, the 5-year cumulative HCC incidence in the derivation cohort was 2.5

INTRODUCTION:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease, and liver biopsy remains the gold standard for diagnosis. However, a subset of patients diagnosed with MASLD by imaging paradoxically exhibit steatosis grade S0 on liver biopsy, posing a diagnostic challenge. This study investigated the outcomes and causes of steatosis 0. METHODS:Steatosis 0 was defined as imaging-detected MASLD with a biopsy-defined steatosis grade S0. We used global cohorts to evaluate outcomes, histologic progression by paired biopsies, and possible causes. The cause analysis included MRI-proton density fat fraction (MRI-PDFF) for fat distribution, pathologist consistency testing, and comparison of serial biopsy sections. RESULTS:In a follow-up cohort of 3,273 biopsy individuals from 16 centers, 123 (3.8%) exhibited steatosis 0. Of these, 29.3% of them had advanced fibrosis (burnt-out MASLD) and demonstrated a risk of liver-related events, whereas those without advanced fibrosis had no such events. In the paired-biopsy cohort of 1,865 patients, 74 (4.0%) individuals initially showed steatosis grade S0; among them, 93.2% retained no or mild steatosis on follow-up biopsy. MRI-PDFF assessments in 42 MASLD patients revealed heterogeneous hepatic fat distribution, with some segments showing steatosis grade S0 despite elevated average liver fat. Interpathologist variability and discrepancies across consecutive biopsy sections contributed to misclassification of steatosis grade. DISCUSSION:Steatosis 0 represents a potential diagnostic gray zone in MASLD. It may be caused by burnt-out MASLD, uneven liver fat distribution, or variability in pathological assessment. Understanding the causes and implications of steatosis 0 is critical for diagnosis and management.

IntroductionThe impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the efficacy and prognosis of pegylated interferon (Peg-IFN)-based therapy for chronic hepatitis B (CHB) remains controversial and requires further investigation.MethodsA total of 620 CHB patients receiving Peg-IFN-based therapy were enrolled and categorized into MASLD-CHB (n = 247) and CHB (n = 373) groups. Propensity score matching (PSM) was employed to balance baseline differences. Kaplan-Meier survival analysis and LASSO-Cox regression were applied to identify independent predictors of complete virological response (CVR) and hepatitis B surface antigen (HBsAg) seroclearance.ResultsAfter PSM, 247 patients were included in each group. Compared with the MASLD-CHB group, the CHB group exhibited significantly higher cumulative CVR rates at month 3 (36.84% vs. 24.54%, p = 0.041), month 12 (77.19% vs. 62.72%, p = 0.013), end of treatment (EOT) (78.94% vs. 65.45%, p = 0.019), and end of follow-up (EOF) (80.70% vs. 68.18%, p = 0.026). The median time to the first CVR was shorter in the CHB group (4.4 vs. 5.5 months, p = 0.030). LASSO-Cox regression revealed HBV DNA (HR: 0.486, 95% CI: 0.297-0.793, p = 0.004), MASLD (HR: 0.736, 95% CI: 0.550-0.986, p = 0.040), HBsAg (HR: 0.808, 95% CI: 0.706-0.926, p = 0.002), HBeAg positivity (HR: 0.611, 95% CI: 0.433-0.862, p = 0.005), and triglycerides (HR: 0.793, 95% CI: 0.661-0.951, p = 0.012) as independent suppressors of CVR. Multiple factors were associated with HBsAg seroclearance (p < 0.05). At the EOF, the MASLD-CHB group had higher liver stiffness measurement values (8.10 [6.40, 9.60] vs. 6.20 [5.00, 7.50]) and a greater proportion of moderate-to-severe fibrosis (18.7% vs. 5.9%, p < 0.01).ConclusionIn CHB patients receiving Peg-IFN-based therapy, concurrent MASLD may impede the reduction of HBV DNA levels, delay the time of first CVR, and potentially accelerate liver fibrosis progression.

BACKGROUND & AIMS:Fibrosis-4 Index (FIB-4) is a noninvasive tool for assessing liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). However, its role of dynamic FIB-4 for assessing fibrosis progression and predicting clinical outcomes remains unclear. The aim of this study was to examine the association between changes in FIB-4 and changes in liver stiffness, fibrosis progression, and outcomes in MASLD. METHODS:Three cohorts were analyzed: VCTE-Prognosis cohort (n = 10,203) for stiffness progression, Paired Liver Biopsy cohort (n = 1,145) for fibrosis progression, and Wenzhou Real-World (WRW) cohort (n = 41,105) for clinical outcomes. Stiffness progression was defined as an increase in liver stiffness measurement, and fibrosis progression by a 1-stage increase. Outcomes included all-cause mortality, cardiovascular events, and liver-related events (LREs). FIB-4 was dichotomized into low (<1.3) and high (≥1.3). Increases were defined as ≥20% rise and to ≥1.3 in the low FIB-4 group, and ≥20% rise in the high FIB-4 group. RESULTS:In the VCTE-Prognosis cohort, stiffness progression was more likely with increasing vs stable FIB-4 (adjusted odds ratio [OR], 2.36; P < .001) in those with low baseline FIB-4. In the high FIB-4 group, stiffness progression rates increased from stable to increasing FIB-4 (adjusted OR, 3.42; P < .001). In the Paired Liver Biopsy cohort, fibrosis progression was more frequent with increasing FIB-4 (adjusted OR, 2.20; P = .004 in low FIB-4; adjusted OR, 3.68; P < .001 in high FIB-4). In the WRW cohort, an increase in dynamic FIB-4 was linked to higher risks for all-cause mortality, cardiovascular events, and LREs (all P < .001). CONCLUSIONS:Dynamic FIB-4 monitoring tracks fibrosis and stiffness progression and predicts clinical outcomes in MASLD.

Objective observe the healthy liver cholesterol-lowering pills for methionine choline lack of feed (Methionine-choline deficient，MCD) diet induced nonalcoholic fatty hepatitis (Nonalcoholic steatohepatitis，NASH) mechanism of lipid metabolism and inflammation in mice. Methods The mice were randomly divided into control group, model group, positive drug group, low, medium and high dose groups of Jianganjiangzhi pills, 10 mice in each group.The control group ate normal diet, and the other experimental groups ate MCD diet.The positive drug group was intritoneally injected with 150mg/kg polyene phosphatidylcholine, the low, medium and high dose groups of Jiangan Jiangzhi pills were administrated with 100 mg/kg, 200 mg/kg and 400 mg/kg respectively, once a day, and the control group and model group were given equal volume of normal saline in parallel.Weigh and record every 7 days.It lasts six weeks.The histopathological changes of liver were observed by HE staining.Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by biochemical kit,The levels of total cholesterol (TC), triglyceride (TG), superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) in liver homogenate were detected by BCA kit.The mRNA expression levels ofNrf2, Ho1, Gclc and Nqo1 in mouse liver tissues were detected by PCR,The expression level ofNRF2 pathway related protein in mouse liver was detected by Western blot . Results Compared with the normal group, the model group had serious liver pathological injury, severe destruction of liver cell structure, widening of cell interval, collapse and infiltration of a large number of inflammatory cells.In the model group, ALT, AST, TG and TC (P<0.01) levels were significantly increased, SOD activity was decreased, MDA level was increased, and GSH-Px activity was decreased. PCR results showed that mRNA expression levels ofNrf2, Ho1, Gclc and Nqo1 in mouse liver tissues were decreased.Westernblot results showed that the relative expression levels ofNRF2, HO-1,GCLC and NQO1 proteins in mice were significantly decreased. Compared with the model group, the liver cell structure of mice in positive drug group (polyene phosphatidylcholine) and Jianggan Jiangzhiwan low-dose, medium-dose and high-dose groups was more clear, with a shorter cell interval and a small amount of inflammatory cell infiltration,ALT, AST,TG and TC levels decreased significantly, SOD activity increased, MDA level decreased, GSH-Px activity increased. The mRNA expression levels ofNrf2, Ho1, Gclc and Nqo1 in liver tissues were increased, and the protein expression levels of NRF2 pathway related proteins were significantly increased. Conclusion Jiangan Jiangzhi pills(健肝降脂丸) can regulate NRF2 pathway to enhance antioxidant capacity and reduce liver steatosis and inflammation in mice with NASH

BACKGROUND Colorectal polyps are commonly observed in patients with chronic liver disease (CLD) and pose a significant clinical concern because of their potential for malignancy. AIM To explore the clinical characteristics of colorectal polyps in patients with CLD, a nomogram was established to predict the presence of adenomatous polyps (AP). METHODS Patients with CLD who underwent colonoscopy at Tianjin Second People’s Hospital from January 2020 to May 2023 were evaluated. Clinical data including laboratory results, colonoscopy findings, and pathology reports were collected. Key variables for the nomogram were identified through least absolute shrinkage and selection operator regression, followed by multivariate logistic regression. The performance of the model was evaluated using the area under the receiver area under curve, as well as calibration curves and decision curve analysis. RESULTS The study enrolled 870 participants who underwent colonoscopy, and the detection rate of AP in patients with CLD was 28.6%. Compared to individuals without polyps, six risk factors were identified as predictors for AP occurrence: Age, male sex, body mass index, alcohol consumption, overlapping metabolic dysfunction-associated steatotic liver disease, and serum ferritin levels. The novel nomogram (AP model) demonstrated an area under curve of 0.801 (95% confidence interval: 0.756-0.845) and 0.785 (95% confidence interval: 0.712-0.858) in the training and validation groups. Calibration curves indicated good agreement among predicted and actual probabilities (training: χ 2 = 11.860, P = 0.157; validation: χ 2 = 7.055, P = 0.530). The decision curve analysis underscored the clinical utility of the nomogram for predicting the risk of AP. CONCLUSION The AP model showed reasonable accuracy and provided a clinical foundation for predicting the occurrence of AP in patients with CLD, which has a certain predictive value.

Prostate cancer (PCa) is the most common non-cutaneous malignancy and the second leading cause of cancer-related death in men. Despite its prevalence, treatment outcomes are often unsatisfactory, necessitating the search for more effective therapeutic approaches. mTOR inhibitor Rapamycin (RAPA) has shown promise in managing PCa, but the emergence of resistance often undermines its long-term effectiveness. Recent studies suggest that poly ADP-ribose polymerase (PARP) inhibitor Olaparib (OLP) may overcome drug resistance in various tumor types. This study aims to assess the efficacy of OLP in treating RAPA-resistant PCa, with a specific focus on elucidating its underlying molecular mechanisms. This study utilized drug exposure and concentration escalation experiments to establish human RAPA-resistant PCa cell line (PC-3R) based on the human PCa cell line (PC-3). PC-3R cell lines were screened through a cloning assay. The efficacy of OLP in RAPA-resistant PCa, as well as its regulatory impact on tumor-associated macrophages (TAMs), was evaluated through a combination of real-time PCR, ELISA, immunohistochemistry, and fluorescence experiments. This study unveiled that the combination of OLP and RAPA effectively suppressed the proliferation, stemness, invasion, angiogenesis, apoptosis resistance, and anti-oxidative stress capacity of RAPA-resistant PCa. Additionally, it demonstrated the capacity of OLP to regulate macrophage polarization within the tumor microenvironment and reverse drug resistance to RAPA in PCa. The findings of this study lay a theoretical foundation for the potential utilization of OLP in the treatment of RAPA-resistant PCa, offering substantial academic significance and promising application prospects.

BACKGROUND:The activation of histone deacetylase 2 (HDAC2) is the main pathogenesis of acute kidney injury (AKI), one of the leading causes of end-stage kidney disease. However, the regulatory role of HDAC2 upregulation on inflammation in AKI is still unclear. RESULTS:In this study, we found that treatment with HDAC2 inhibitor BRD6688 could mitigate the degree of mesangial sclerosis, interstitial infiltration and tubular atrophy, reduce the concentration of blood urea nitrogen (BUN) and serum creatinine (Scr), improve the proliferation, anti-apoptotic, anti-oxidative stress and angiogenesis effects of renal cells. Our results mainly indicated that renal HDAC2 activity was increased by casein kinase 2 (CK2) in renal ischemia reperfusion (I/R) models, and HDAC2 genetic ablation in HREpiC cells suppressed the leukotriene B4 (LTB4) production. Renal leukotriene A4 hydrolase (LTA4H) activity was increased in AKI mice in a HDAC2-dependent manner. LTB4 could induce monocytes to differentiate into M1 macrophages, while BRD6688 could suppress this effect and force the M1 macrophages polarize to M2 macrophages. CONCLUSION:Inhibition of HDAC2 activities by BRD6688 could suppress the progression of renal I/R injury through the regulation of LTA4H and macrophage polarization.

Background/Objectives:Metabolic dysfunction-associated fatty liver disease (MAFLD) is highly prevalent in China. Clinical evidence supporting the role of polyenyl phosphatidylcholine (PPC) in delaying liver fibrosis in patients with MAFLD is limited. Hence this study evaluated the effectiveness of PPC and its association with delaying progression of liver fibrosis in patients with MAFLD in China. Methods:This multicenter, retrospective observational study included patients with type 2 diabetes mellitus or ≥2 metabolic dysregulations. Patients from the MAFLD cohort were divided into two groups to receive either PPC or control (no hepatoprotective treatment). The primary endpoint was the change in baseline fibrosis (FIB)-4 index at 12 and 24 weeks. The secondary endpoint involved comparison of changes in liver enzymes and blood lipid levels. Results:Among 22,705 patients with MAFLD who were treated with hepatoprotective drugs, 7,093 received PPC. Significant reduction in baseline fibrosis was observed at 24 weeks (PPC: -0.12 ± 0.62 vs. control: 0.11 ± 0.50, p = 0.034). Baseline aspartate aminotransferase (AST) levels significantly improved at 12 weeks (PPC: -6.25 ± 15.18 vs. control: -2.41 ± 15.40; p = 0.0392). In the PPC group, baseline alanine transaminase (ALT) levels decreased at 12- and 24-weeks compared to those of the control group, but results were not significant. PPC significantly reduced baseline total bilirubin at 12 weeks (p = 0.0122) and 24 weeks (p = 0.0010), and low-density lipoprotein cholesterol levels at 12 weeks (p = 0.0442). Conclusion:PPC treatment can lower the risk of liver fibrosis and improve liver function and lipid profiles. Further validation is warranted in other ethnic groups in larger cohorts.

BACKGROUND AND AIMS:Type 2 diabetes mellitus (T2DM), hepatic steatosis (HS), and chronic hepatitis B (CHB) frequently co-exist, but the association of T2DM with liver histology has not been well characterized. The study investigated the impact of T2DM on the presence and severity of liver fibrosis and inflammation in CHB patients with biopsy-proven HS (CHB-HS). APPROACH AND RESULTS:We enrolled CHB-HS patients who underwent liver biopsy from 19 medical centers (5 countries/regions) from 1990 to 2024. Propensity score matching (PSM) on age, sex, HBeAg, and HBV DNA levels was performed to balance background risks between CHB-HS patients with and without T2DM in a 1:3 ratio. The study included 1019 CHB-HS patients (mean age 40.3±10.4 years, 75.4% male, 10.5% T2DM). In the PSM cohort (106 T2DM, 320 non-T2DM), T2DM patients (vs. non-T2DM) had higher proportions with significant (stage ≥2) fibrosis (62.3% vs. 42.2%, p <0.01) but not with significant hepatic inflammation or moderate-to-severe steatosis (grade ≥2 for both). On multivariable logistic regression analyses, T2DM was an independent factor associated with significant fibrosis (aOR 1.86, 95% CI: 1.15-3.01, p =0.01), but not other components of metabolic syndrome. Meanwhile, HBeAg + and body mass index (BMI) rather than T2DM were associated with significant hepatic inflammation and moderate-to-severe steatosis, respectively, with similar findings in the total pre-PSM cohort. CONCLUSIONS:In CHB patients with concurrent HS, T2DM was an independent factor associated with significant fibrosis, HBeAg+ with hepatic inflammation, and BMI with moderate-to-severe steatosis, suggesting that both viral and metabolic control are crucial in the management of CHB patients with HS.

Metabolic associated fatty liver disease (MAFLD) represents a significant public health concern. Previous studies have shown that ACT001 has therapeutic effects on MAFLD. This study investigated the potential mechanisms by which ACT001 may treat MAFLD through an integrated approach of transcriptomics and metabolomics. MAFLD model induced by high-fat diet was established, and ACT001 was given by gavage. Histological analysis was performed, and liver enzyme and lipid levels were measured. Transcriptomic analysis was performed to identify differentially expressed genes, while metabolomic analysis was used to detect differential metabolites. Pathways enriched by genes and metabolites affected by ACT001 were also identified. The differentially expressed genes were confirmed through RT-qPCR. ACT001 reduced the levels of liver enzymes and lipids, and alleviated pathological damage such as hepatic steatosis. The integration of transcriptomic and metabolomic analyses indicated that ACT001 may alleviate high-fat diet-induced MAFLD by regulating the linoleic acid and glutathione metabolic pathways. The validation of five differentially expressed genes using RT-qPCR yielded results that were consistent with the transcriptomics data. ACT001 may exert a therapeutic effect in MAFLD mice by modulating glutathione metabolism and linoleic acid metabolism. It has the potential to be a promising treatment for MAFLD.

BACKGROUND:Non-invasive assessment of improvement in fibrotic metabolic dysfunction-associated steatohepatitis (MASH) is an important clinical problem. We aimed to develop and validate the fibrotic MASH resolutionVCTE index, a non-invasive tool for identifying fibrotic MASH resolution and predicting liver-related events (LREs). METHODS:We collected data from 2,017 individuals who had two liver biopsies, separated in time, across 40 centers in the first dataset. This dataset included two independent cohorts, which were used to develop and externally validate the tool (including the baseline and change in acFibroMASH index plus change in serum alanine aminotransferase levels). The second independent dataset, comprising 17,949 patients who underwent vibration-controlled transient elastography (VCTE) at 16 centers, was used to examine associations between the developed index and the risk of incident LREs. FINDINGS:After application of the inclusion and exclusion criteria, 252 and 8,752 patients were included in the first and second datasets, respectively. The fibrotic MASH resolutionVCTE index accurately identified fibrotic MASH resolution with an area under the receiver operating curve (AUROC) of 0.82 (95% CI 0.74-0.90) in the derivation cohort and 0.80 (95% CI 0.72-0.88) in the validation cohort. Patients with a fibrotic MASH resolutionVCTE index >0.61 had a substantially lower risk of incident LREs than those with an index <0.24 (adjusted-hazard ratio 0.043). The index achieved AUROCs of 0.86 and 0.87, respectively, for predicting the 5- and 10-year probability of not developing LREs. CONCLUSIONS:This global multicenter study suggests that the fibrotic MASH resolutionVCTE index may offer a non-invasive approach to estimate fibrotic MASH resolution and stratify long-term risk of LREs. FUNDING:National Natural Science Foundation.

BACKGROUND AND AIMS:HCC poses a significant global health burden, with HBV being the predominant etiology in China. However, current diagnostic markers lack the requisite sensitivity and specificity. This study aims to develop and validate serum N-glycomics-based models for the diagnosis and prognosis of HCC in patients with chronic hepatitis B-related cirrhosis. APPROACH AND RESULTS:This study enrolled a total of 397 patients with chronic hepatitis B-related cirrhosis and HCC for clinical management. N-glycomics profiling was conducted on all participants, and clinical data were collected. First, machine learning-based models, Hepatocellular Carcinoma Glycomics Random Forest model and Hepatocellular Carcinoma Glycomics Support Vector Machine model, were established for early screening and diagnosis of HCC using N-glycomics. The AUC values in the validation set were 0.967 (95% CI: 0.930-1.000) and 0.908 (0.840-0.976) for Hepatocellular Carcinoma Glycomics Random Forest model and Hepatocellular Carcinoma Glycomics Support Vector Machine model, respectively, outperforming AFP (0.687 [0.575-0.765]) and Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) (0.665 [0.507-0.823]). It also showed superiority in subgroup analysis and external validation. Calibration and decision curve analysis also showed good predictive performance. Additionally, we developed a prognostic model, the prog-G model, based on N-glycans to monitor recurrence in patients with HCC after curative treatment. During the follow-up period, it was observed that this model correlated with the clinical condition of the patients and could identify all recurrent HCC cases (n=12) prior to imaging findings, outperforming AFP (n=7) and PIVKA-II (n=9), while also detecting recurrent lesions earlier than imaging. CONCLUSIONS:N-glycomics models can effectively predict the occurrence and recurrence of HCC to improving the efficiency of clinical decision-making and promoting the precision treatment of HCC.

The efficacy and safety of a lower dose of vitamin E for metabolic dysfunction-associated steatohepatitis (MASH) treatment are unclear. This multi-center, randomized, double-blind, placebo-controlled study includes 124 non-diabetic participants with biopsy-proven MASH. Participants are randomly assigned to receive oral vitamin E 300 mg or the placebo in a 1:1 ratio. The primary outcome is improvement in hepatic histology. In the modified intention-to-treat population, 29.3% of participants in the vitamin E group achieve the primary outcome compared with 14.1% in the placebo group. Significant improvement in steatosis, lobular inflammation, and fibrosis stages is observed in the vitamin E group. 12 serious adverse events are reported in this trial but are not considered to be related to the treatment. Vitamin E 300 mg daily achieves sound improvements in liver histology in the Chinese population with MASH. This study is registered at ClinicalTrials.gov (NCT02962297).

Background and objectiveACT001 is a novel sesquiterpene lactone derivative with noteworthy antineoplastic and anti-inflammatory properties. This study aimed to investigate the efficacy of ACT001 against metabolic dysfunction associated steatotic liver disease (MASLD) pathogenesis in two established murine models, and to elucidate its regulatory role in the gut microbiota-bile acid-FXR axis.Materials and methodsA high-fat diet (HFD) and a methionine-choline-deficient (MCD) diet induced two MASLD models in C57BL/6J mice. Histological analysis was performed, biochemical indices were measured, and the expression of tight junctions and farnesoid X receptor (FXR)-related pathways was detected. Gut microbiota was assessed by 16S rDNA sequencing, while bile acids (BAs) in fecal samples were analyzed using UPLC/MS-MS.ResultsACT001 decreased liver injury, alleviated hepatic lipid accumulation, and restored intestinal barrier integrity. Furthermore, 16S rDNA illustrated that ACT001 could partially rebalance intestinal dysbacteriosis and upregulate the relative abundance of various bacteria, especially Clostridium and Erysipelotrichaceae_Clostridium. Moreover, ACT001 facilitated the generation of uncombined BAs and accumulated specific BAs within the ileum, such as 23-Nor-deoxycholic acid (23-DCA) and lithocholic acid-3-sulfate (LCA-3S), which had a downregulation effect on the expression of the enteral FXR-fibroblast growth factor 15 (FGF15) pathway.ConclusionACT001 exerted a multifactorial therapeutic effect on MASLD, potentially linked to the regulation of the gut microbiota-BAs-FXR axis. Thus, it has the potential to be an effective treatment for MASLD.

BACKGROUND & AIMS:Hypertension is common in metabolic dysfunction-associated steatotic liver disease (MASLD), but its impact on long-term clinical outcomes and disease progression remains unclear. This study investigated the association of hypertension with the risk of adverse clinical outcomes and progression of liver stiffness/fibrosis in MASLD. METHODS:Three multicenter large cohorts were analyzed: the UK Biobank (UKBB) cohort to assess the risk of adverse clinical outcomes, the VCTE-Prognosis cohort to assess liver stiffness/fibrosis progression, and the Paired Liver Biopsy cohort to assess histologic liver fibrosis progression. Adverse clinical outcomes were defined as all-cause mortality, cardiovascular events, and/or liver-related events. Liver stiffness progression was defined as an increase in liver stiffness measurement from <10 kPa to ≥10 kPa or an increase of ≥20% for baseline liver stiffness measurement ≥10 kPa. Liver fibrosis progression was defined as a 1-stage fibrosis stage increase. Cox regression and Kaplan-Meier analyses were used to evaluate the impact of baseline hypertension on outcomes. RESULTS:A total of 107,316 adults from the UKBB cohort, 8,169 from the VCTE-Prognosis cohort, and 1,670 from the Paired Liver Biopsy cohort were included. The prevalence of hypertension was 37.1%, 33.4%, and 48.9%, respectively. In the UKBB cohort, hypertension was associated with long-term adverse clinical outcomes (adjusted hazard ratio [HR] 1.30, 95% CI 1.26-1.33, p <0.001). In the VCTE-Prognosis cohort, hypertension was associated with a higher risk of liver stiffness progression (adjusted HR 1.57, 95% CI 1.30-1.90, p <0.001), while in the Paired Liver Biopsy cohort, hypertension was associated with a greater risk of histologic liver fibrosis progression (adjusted HR 1.41, 95% CI 1.12-1.78, p = 0.004). Subgroup and sensitivity analyses supported these findings. CONCLUSIONS:Hypertension is a modifiable risk factor that increases the risk of adverse clinical outcomes and progression of liver stiffness and fibrosis in MASLD. IMPACT AND IMPLICATIONS:This study provides robust evidence from three large multicenter cohorts demonstrating that hypertension is independently associated with increased risks of adverse clinical outcomes and liver fibrosis progression in individuals with MASLD. These findings reveal that hypertension, traditionally managed from a cardiovascular perspective, also plays a critical and underrecognized role in liver disease progression, making them highly relevant for hepatologists, cardiologists, and primary care providers. Incorporating non-invasive fibrosis assessments into routine care for patients with MASLD and hypertension may facilitate early risk stratification and support targeted interventions to reduce both hepatic and cardiovascular complications.

Abstract Background and aims:Hepatitis C virus (HCV) associated cirrhosis are in high risk of hepatocellular carcinoma (HCC), and this study aimed to explore the risk factors, and establish and validate a novel nomogram. Methods: A total of 309 inpatients with HCV- associated cirrhosis from Tianjin Second People's Hospital were selected as the training cohort, and 363 patients from Beijing You’an Hospital were selected as the validation cohort. Both cohorts received Direct-Acting Antiviral Agents (DAAs) treatment and achieved sustained virological response (SVR). Laboratory parameters were collected at baseline and duration of follow-up. Cox regression analysis was used to explore risk factors of HCC, and a nomogram for prediction was developed and validated. Results: HCC incidence was 5.45 100PY (95% CI, 3.91-7.40) in patients of the training cohort. Age, nonspecific liver nodules, the albumin-Bilirubin (ALBI) score and end of treatment (EOT)-AFP are independent risk factors for HCC by Cox regression analysis. A nomogram was used to predict the 1-year, 3-year and 5-year incidence of HCC, with the areas under receiver operating characteristic curves (AUROCs) of 0.866, 0.813 and 0.764, respectively. The AUROCs in validation cohort at 1, 3, and 5 years were 0.884, 0.783 and 0.692 in this nomogram, respectively. Conclusion: This novel nomogram had a good predictive ability for HCC in patients with HCV-associated cirrhosis after eliminating virus with direct-acting antiviral agents, especially in 3 years.