Hepatic fibrosis is a common pathological process involving persistent liver injury with various etiologies and subsequent inflammatory responses that occur in chronic liver diseases. If left untreated, liver fibrosis can progress to liver cirrhosis, hepatocellular carcinoma and eventually, liver failure. Unfortunately, to date, there is no effective treatment for liver fibrosis, with the exception of liver transplantation. Although the pathophysiology of liver fibrosis is multifactorial and includes the activation of hepatic stellate cells, which are known to drive liver fibrogenesis, hepatic macrophages have emerged as central players in the development of liver fibrosis and regression. Hepatic macrophages, which consist of resident macrophages (Kupffer cells) and monocyte‐derived macrophages, have been shown to play an intricate role in the initiation of inflammatory responses to liver injury, progression of fibrosis, and promotion of fibrosis resolution. These features have made hepatic macrophages uniquely attractive therapeutic targets in the fight against hepatic fibrosis. In this review, we synthesised the literature to highlight the functions and regulation of heterogeneity in hepatic macrophages. Furthermore, using the existing findings, we attempt to offer insights into the molecular mechanisms underlying the phenotypic switch from fibrogenic macrophages to restorative macrophages, the regulation of heterogeneity, and modes of action for hepatic macrophages. A better understanding of these mechanisms may guide the development of novel anti‐fibrotic therapies (eg macrophage subset‐targeted treatments) to combat liver fibrosis in the future.

Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2⁺ACE2⁺ small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2⁺ACE2⁺ cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27⁺ memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2⁺ACE2⁺ small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2⁺ACE2⁺ cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.

Sorcin induces gastric cancer cell migration and invasion contributing to STAT3 activation Sorcin induces gastric cancer cell migration and invasion contributing to STAT3 activation

Bromodomain-containing protein 4 (BRD4) has been implicated to play a regulatory role in fibrogenic gene expression in animal models of liver fibrosis. The potential role of BRD4 in liver fibrosis in humans remains unclear. We sought to investigate the expression and cellular localization of BRD4 in fibrotic liver tissues. Human liver tissues were collected from healthy individuals and patients with liver fibrosis of various etiologies. RNA-seq showed that hepatic BRD4 mRNA was elevated in patients with liver fibrosis compared with that in healthy controls. Subsequent multiple manipulations such as western blotting, real-time quantitative polymerase chain reaction, and dual immunofluorescence analysis confirmed the abnormal elevation of the BRD4 expression in liver fibrosis of various etiologies compared to healthy controls. BRD4 expression was positively correlated with the severity of liver fibrosis, and also correlated with the serum levels of aspartate aminotransferase and total bilirubin. Moreover, the expression of C-X-C motif chemokine ligand 6 (CXCL6), a factor interplayed with BRD4, was increased in hepatic tissues of the patients with liver fibrosis. Its expression level was positively correlated with BRD4 level. BRD4 is up-regulated in liver fibrosis, regardless of etiology, and its increased expression is positively correlated with higher degrees of liver fibrosis. Our data indicate that BRD4 play a critical role in the progress of liver fibrosis, and it holds promise as a potential target for intervention of liver fibrosis.

Background: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, with unclear pathogenesis. Although immune disorders, especially T cell infiltration, are thought to play a vital role in PSC, the specific pathogenesis mechanisms remain incompletely understood. This study evaluated the potential key gene associated with the PSC pathogenesis and analyzed the associations of the key gene with prognosis and immune cell infiltration by combining bioinformatics analysis and experimental verification. Methods: Transcriptome data of PSC and normal human liver tissues (GSE159676) were obtained from the gene expression omnibus database. Differentially expressed genes (DEGs) were identified, and differences in biological states were analyzed. A protein–protein interaction (PPI) network was constructed. Hub genes were identified, and their expression was verified using transcriptome data of mice fed 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and Mdr2^−/− mice (GSE179993, GSE80776), as well as by immunohistochemistry staining on clinical samples. The correlations between the key gene and other factors were evaluated by Pearson’s correlation coefficient. Immune cell infiltration into human liver (GSE159676) was analyzed by xCell and verified by immunofluorescence staining on PSC liver samples. Results: Of the 185 DEGs identified, 113 were upregulated and 72 were downregulated genes in PSC. Genes associated with immune cell infiltration and fibrosis were significantly enriched in PSC. PPI network showed close interactions among DEGs. A module strongly associated with immune infiltration was identified, with annexin A1 (ANXA1) being the core gene. High expression of ANXA1 in PSC was confirmed in two public datasets and by immunohistochemistry staining on clinical samples. High ANXA1 expression was strongly associated with high-risk score for PSC. Also, ANXA1 expression was positively associated with chemokines and chemokine receptors and with the infiltration of immune cells, especially T cells, into liver with PSC. Immune infiltration, fibrosis, and cancer-related processes were markedly enriched in PSC with high expression of ANXA1. Conclusion: ANXA1 is a key gene associated with high risk and infiltration of immune cells, especially T cells, in PSC. These findings provide new insight into the key biomarker of PSC and suggest that targeting ANXA1 may be a valuable strategy for the treatment of PSC.