Yue Li

During chronic liver injury, hepatocytes promote liver fibrosis by interacting with hepatic stellate cells (HSCs). However, the key intracellular factors that regulate intercellular communication in hepatocytes remain poorly understood. Although cluster of differentiation 146 (CD146) is predominantly recognized as an endothelial cell marker, our study found that CD146 is substantially upregulated in hepatocytes under fibrotic stress and may play an independent role in transcellular signaling. This study aimed to elucidate the functions and underlying mechanisms of hepatocyte CD146 in liver fibrosis. We evaluated CD146 expression in liver tissues and serum soluble CD146 (sCD146) levels in patients with liver fibrosis and mouse models. Hepatocyte-specific CD146-overexpressing mice (AAV8-CD146) were generated and fed either a normal chow diet (NCD) or a high-fat diet (HFD); hepatocyte-specific CD146 knockout mice (CD146^Alb-Cre) were subjected to carbon tetrachloride (CCl₄)-induced fibrosis. Comprehensive molecular, biochemical, and histological analyses were performed to systematically assess the role of CD146 in the initiation and progression of liver fibrosis. A co-culture system of hepatocytes and HSCs was also established to investigate the paracrine regulatory effects of CD146 on HSCs. The levels of sCD146 were positively correlated with the progression and severity of chronic liver disease. A diagnostic model incorporating sCD146 and other serological markers showed improved diagnostic performance for decompensated cirrhosis. Compared with healthy controls, hepatocyte CD146 expression was markedly upregulated in liver tissues from patients with cirrhosis and fibrotic mice. Under HFD conditions, hepatocyte-specific CD146 overexpression exacerbated hepatic inflammation and fibrosis in mice, whereas hepatocyte-specific CD146 deletion significantly attenuated CCl₄-induced liver fibrosis. Transforming growth factor-β1 (TGF-β1) induced CD146 upregulation in hepatocytes and increased the release of sCD146. Released sCD146 bound to integrin αvβ1 on the surface of HSCs, activated the p38 mitogen-activated protein kinase (p38 MAPK) pathway, and promoted HSC activation and type I collagen production. These findings identify hepatocyte-derived CD146/sCD146 as a TGF-β1-inducible mediator of hepatocyte-HSC communication that promotes liver fibrosis through the CD146/sCD146-integrin αvβ1-p38 MAPK signaling axis. They also support serum sCD146 as a potential non-invasive biomarker for advanced chronic liver disease.

Background: The reversal of liver fibrosis is crucial for improving outcomes in chronic liver disease. The gut–liver axis, mediated by the intestinal microbiota, plays a significant role in this process. However, its dynamic changes and mechanisms during reversal remain unclear. This study aimed to systematically reveal these dynamics and explore the link between gut microbiota and metabolism in a spontaneous reversal model. Methods: Intestinal contents were collected from mouse model groups (fibrosis, 4-week reversal, and 12-week reversal). The use of 16S rRNA gene sequencing was employed to analyze gut microbiota structure, and untargeted metabolomics was used to profile metabolic changes. Differential metabolites and microbial taxa were identified using multivariate statistical analysis, followed by pathway enrichment analysis. Spearman correlation analysis was used to construct metabolite–microbiota association networks across different reversal stages. Results: Metabolomic analysis showed significant alterations in multiple pathways during reversal. Linoleic and α-linolenic acid metabolism had a high impact in later stages. Taurine and biotin metabolism remained active throughout. Branched-chain amino acid degradation was enriched later. Microbiota analysis revealed significant structural shifts via beta-diversity. Bacteroidota decreased while Firmicutes increased in 4 weeks. Butyrate-producing families increased, and Akkermansia was enriched later. Integrated analysis demonstrated significant correlations between specific bacteria and metabolites, indicating a close microbiota–metabolism association during reversal. Conclusions: This integrated multi-omics study delineates the potential dynamic reorganization of the gut microbiota and host metabolism during spontaneous liver fibrosis reversal. These findings provide a theoretical basis for understanding the gut–liver axis mechanism in fibrosis reversal and for developing microbiota-targeted intervention strategies.

This study aims to explore the effects of various hepatic steatosis conditions on histological outcomes in patients with significant inflammation and fibrosis in chronic hepatitis B (CHB) and analyze their impact on HBV virological suppression outcomes and biochemical improvement. This retrospective study included 219 chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogues therapy. Each of these patients underwent two liver biopsies. Patients were categorized into four groups based on hepatic steatosis status: sustained non-hepatic steatosis (n = 118), new-onset hepatic steatosis (n = 33), sustained hepatic steatosis (n = 37), and disappeared hepatic steatosis (n = 31). We compared the liver biochemical parameters and histological changes before and after treatment. Logistic regression analysis was performed to evaluate characteristics associated with the improvement of significant liver inflammation (G ≥ 2), significant fibrosis (S ≥ 2), and the persistence of hepatic steatosis. After treatment, the sustained non-steatosis group exhibited the highest rate of improvement in baseline significant inflammation (75.31%), while the sustained steatosis group had the lowest (42.31%, p = 0.008). The sustained steatosis group also had the highest rate of inflammation progression (15.38%, p = 0.020) and was identified as a risk factor for inadequate baseline inflammation improvement (p = 0.006, OR = 0.244, 95% CI 0.090–0.665). In terms of baseline significant liver fibrosis improvement, the sustained non-hepatic steatosis group showed the highest improvement rate (67.14%), while the sustained hepatic steatosis group had the lowest (28.00%, p = 0.006). The new-onset steatosis group had the highest rate of liver fibrosis progression (15.00%, p = 0.027), and sustained hepatic steatosis was a risk factor for poor baseline fibrosis improvement (p = 0.001, OR = 0.180, 95% CI 0.064–0.507). Furthermore, the sustained hepatic steatosis group showed the smallest decrease in liver enzyme markers ALT, GGT, and ALP post-treatment, with reductions of 22.11% (p = 0.023), 13.86% (p = 0.003), and 1.98% (p = 0.025), respectively. Logistic regression analysis revealed that high baseline BMI and LDL-C levels were significantly associated with persistent fatty liver, with high BMI (p = 0.042, OR = 1.109, 95% CI 1.004–1.226) and high LDL-C (p < 0.001, OR = 2.570, 95% CI 1.524–4.332). In CHB patients with significant inflammation and fibrosis, the persistence of hepatic steatosis during antiviral treatment may impede the improvement of inflammation and fibrosis, leading to disease progression and biochemical abnormalities.

Nonalcoholic steatohepatitis (NASH) is closely related to liver fibrosis. The role of coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) in NASH remains unknown. CHCHD2’s functions as a transcription factor have received much less attention than those in mitochondria. Herein, we systematically characterized the role of CHCHD2 as a transcription factor by chromatin immunoprecipitation sequencing and found its target genes were enriched in nonalcoholic fatty liver disease (NAFLD). Overall, CHCHD2 expression was found to be increased in the livers of patients with NAFLD and those of NASH mice. In line with these findings, CHCHD2 deficiency ameliorated NASH- and thioacetamide-induced liver fibrosis, whereas hepatocyte-specific CHCHD2 overexpression promoted liver fibrosis in NASH mice via Notch signaling. Specifically, CHCHD2-overexpressing hepatocytes activated hepatic stellate cells by upregulating osteopontin levels, a downstream mediator of Notch signals. Moreover, Notch inhibition attenuated CHCHD2 overexpression–induced liver fibrosis in vivo and in vitro. Then we found lipopolysaccharide-induced CHCHD2 expression in hepatocytes was reverted by verteporfin, an inhibitor that disrupts the interaction between Yes-associated protein (YAP) and transcriptional enhanced associate domains (TEADs). In addition, CHCHD2 levels were positively correlated with those of TEAD1 in human samples. In conclusion, CHCHD2 is upregulated via YAP/TAZ-TEAD in NASH livers and consequently promotes liver fibrosis by activating the Notch pathway and enhancing osteopontin production.

Background: Non-alcoholic fatty liver disease (NAFLD) is a widespread disease, but no recognized drug treatment exists. Previous studies have shown that artemether (Art) can ameliorate carbon tetrachloride (CCl₄)–induced liver fibrosis in mice. This study sets out to observe the therapeutic impact of Art on non-alcoholic steatohepatitis (NASH).Methods: Model mice were provided with a methionine- and choline-deficient (MCD) diet for 4 weeks or a high-fat diet (HFD) for 28 weeks, respectively, and then treated with Art. RNA sequencing (RNA-Seq) analyzed gene expression changes caused by Art treatment. The molecular mechanism of the therapeutic effects of Art on NASH was studied in the mouse liver and HepG2 cells.Results: Art treatment significantly attenuated hepatic lipid accumulation and liver damage in MCD diet– or HFD-induced NASH mice. The RNA-Seq analysis revealed lipid metabolism as a major pathway suppressed by Art administration, in addition to the regulation of inflammation pathways. Mechanistically, Art reduced lipid accumulation by repressing de novo lipogenesis of sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD1), promoting lipolysis of peroxisome proliferator–activated receptor-γ co-activator-1α (PGC1α), adipose triglyceride lipase (ATGL), and carnitine palmitoyltransferase I (CPT-1a) in NASH mouse liver and HepG2 cells. In addition, Art inhibited the secretion of pro-inflammatory factors and reduced inflammatory infiltration by effectively inhibiting M1 macrophage activation. Furthermore, Art inhibited transforming growth factor-beta 1 (TGF-β), and the SMAD signaling pathway mediates the development of liver fibrosis.Inclusion: Art improved fat deposition by repressing de novo lipogenesis and promoting lipolysis in vivo and in vitro. Furthermore, Art improved inflammation and fibrosis with a significant effect. It is a prospective therapeutic agent for NASH.

Results: One new stereoisomer of biphenylneolignan with four known compounds was isolated from the leaves of Patrinia villosa Juss. Methods: The structure of the new compound was elucidated as 2,6,2',6'-tetramethoxy-4,4'-bis (1,2-trans-2,3-epoxy-1-hydroxypropyl) biphenyl (1) on the basis of spectroscopic analysis and comparison with literature data. The four known compounds were identified as 2,6,2',6'-tetramethoxy-4,4'-bis(1,2-cis-2,3-epoxy-1-hydroxypropyl)biphenyl (2), 1H-indole-3-carbaldehyde (3), luteolin (4) and quercetin(5) by comparison of their spectral data with the reported data, respectively. Conclusions: Compound 1 is a new biphenylneolignan, compound 2 and 3 were isolated for the first time from the plant.

Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a remarkable protein as it clearly plays multiple roles in mediating viral replication, host-cell interactions and viral pathogenesis. However, on the impact of cell growth, there have been different study results. NS5ATP9, also known as KIAA0101, p15PAF, L5, and OEACT-1, was first identified as a proliferating cell nuclear antigen-binding protein. Earlier studies have shown that NS5ATP9 might play an important role in HCV infection. The aim of this study is to investigate the function of NS5ATP9 on hepatocellular carcinoma (HCC) cell lines proliferation under HCV NS5A expression. The results showed that overexpression of NS5ATP9 inhibited the proliferation of Bel7402 cells, whereas knockdown of NS5ATP9 by interfering RNA promoted the growth of HepG2 cells. Under HCV NS5A expression, RNA interference (RNAi) targeting of NS5ATP9 could reverse the inhibition of HepG2 cell proliferation, suggesting that NS5ATP9 might be an anti-proliferation gene that plays an important role in the suppression of cell growth mediated by HCV NS5A via MEK/ERK signaling pathway. These findings might provide new insights into HCV NS5A and NS5ATP9.