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Background: Gallbladder cancer (GC) is a malignant disease characterized with highly cellular heterogeneity and poor prognosis. Determining the intratumoral heterogeneity and microenvironment (TME) can provide novel therapeutic strategies for GC. Methods: We performed the single‐cell RNA sequencing on the primary and lymph node metastatic gallbladder tumors and the adjacent normal tissues of five patients. The transcriptomic atlas and ligand–receptor‐based intercellular communication networks of the single cells were characterized. Results: The transcriptomic landscape of 24,887 single cells was obtained and characterized as 10 cellular clusters, including epithelial, neuroendocrine tumor cells, T&NK cells, B cells, RGS5+ fibroblasts, POSTN+ fibroblasts, PDGFRA+ fibroblasts, endothelial, myeloid cells, and mast cells. Different types of GC harbored distinct epithelial tumor subpopulations, and squamous cell carcinoma could be differentiated from adenocarcinoma cells. Abundant immune cells infiltrated into adenocarcinoma and squamous cell carcinoma, rather than neuroendocrine neoplasms, which showed significant enrichment of stromal cells. CD4+/FOXP3+ T‐reg and CD4+/CXCL13+ T helper cells with higher exhausting biomarkers, as well as a dynamic lineage transition of tumor‐associated macrophages from CCL20hi/CD163lo, CCL20lo/CD163hi to APOE+, were identified in GC tissues, suggesting the immunosuppressive and tumor‐promoting status of immune cells in TME. Two distinct endothelial cells (KDR+ and ACKR1+), which were involved in angiogenesis and lymphangiogenesis, showed remarkable ligand–receptor interactions with primary GC cells and macrophages in gallbladder tumors. Conclusions: This study reveals a widespread reprogramming across multiple cell populations in GC progression, dissects the cellular heterogeneity and interactions in gallbladder TME, and provides potential therapeutic targets for GC. [ABSTRACT FROM AUTHOR]

Helicobacter pylori infection induces gastric cancer (GC) development through a progressive cascade; however, the roles of the microRNAs that are involved in the cascade and the underlying mechanisms are still unclear. Here, we found that microRNA-204 was suppressed in gastric mucosal cells in response to H.pylori infection and downregulated in GC tissues due to aberrant methylation of the promoter of its host gene, TRPM3. Helicobacter pylori induced a progressive downregulation of microRNA-204 from superficial gastritis to intestinal metaplasia, with an accompanying increment of the methylated levels of CpG sites in the TRPM3 promoter. With the GC cellular models of AGS, MGC-803 or BGC-823, we found that microRNA-204 suppressed the tumor necrosis factor (TNF)-α-induced activation of NF-κB signaling pathways and, in animal models, inhibited tumor growth and metastasis. The conditional supernatant of microRNA-204 overexpression GC cells led to reduced tube formation of human umbilical vein endothelial cells. A target gene for microRNA-204 was BIRC2 , and in GC cells, BIRC2 knockdown recapitulated the biological phenotype of microRNA-204 overexpression. BIRC2 overexpression promoted the metastasis of GC cells and rescued the inhibition activities of microRNA-204 on cell migration and the NF-κB signaling pathway. Moreover, lower microRNA-204 and higher BIRC2 expression levels were associated with a poorer prognosis of GC patients. These results demonstrate that epigenetic silencing of microRNA-204 induced by H.pylori infection augments the NF-κB signaling pathway in H.pylori -induced gastritis and GC, potentially providing novel intervention targets for these diseases. MicroRNA-204 was epigenetically down-regulated by H. pylori infection in gastric mucosal cells. It led to enhanced BIRC2 expression level and BIRC2/TNF-a/NF-kB signaling pathway activities, which promoted angiogenesis and metastasis of gastric cancer cells. [ABSTRACT FROM AUTHOR]

Cadmium has been defined as type I carcinogen for humans, but the underlying mechanisms of its carcinogenic activity and its influence on protein-protein interactions in cells are not fully elucidated. The aim of the current study was to evaluate, systematically, the carcinogenic activity of cadmium with systems biology approaches. From a literature search of 209 studies that performed with cellular models, 208 proteins influenced by cadmium exposure were identified. All of these were assessed by Western blotting and were recognized as key nodes in network analyses. The protein-protein functional interaction networks were constructed with NetBox software and visualized with Cytoscape software. These cadmium-rewired genes were used to construct a scale-free, highly connected biological protein interaction network with 850 nodes and 8770 edges. Of the network, nine key modules were identified and 60 key signaling pathways, including the estrogen, RAS, PI3K-Akt, NF-κB, HIF-1α, Jak-STAT, and TGF-β signaling pathways, were significantly enriched. With breast cancer, colorectal and prostate cancer cellular models, we validated the key node genes in the network that had been previously reported or inferred form the network by Western blotting methods, including STAT3, JNK, p38, SMAD2/3, P65, AKT1, and HIF-1α. These results suggested the established network was robust and provided a systematic view of the carcinogenic activities of cadmium in human. [ABSTRACT FROM AUTHOR]

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid commonly used for treating cholestatic liver disease. However, its efficacy on non-alcoholic steatohepatitis (NASH) was controversial. This study aimed to investigate the impact of a high dosage of UDCA on a mouse model of NASH. Forty 6-week-old mice were fed a high-fat high-cholesterol (HFHC) diet for 12 weeks to establish a mouse model of NASH, and then divided into four groups: two groups transitioned to a normal diet, and the other two groups maintained the HFHC diet. Each group was administered a daily dosage of 300 mg/kg of UDCA or saline for a period of 8 weeks. The 16 s ribosomal RNA genes extracted from mice fecal pellets were sequenced using next-generation sequencing techniques. Serum bile acid profiles were quantified using liquid chromatography electrospray ionization tandem mass spectrometry method. The results showed that UDCA treatment ameliorated liver inflammation, without affecting liver fibrosis. UDCA treatment reduced the relative abundance of the genera Bacteroides, Parabacteroides, and Intestinimonas , whereas increased the relative abundance of the genera norank_f_Muribaculaceae and Parasutterella in the HFHC-maintaining groups. The serum levels of total bile acids and total primary bile acids increased, whereas those of endogenous primary bile acids decreased after UDCA treatment. Correlation analysis showed that primary bile acids were negatively correlated with the genera norank_f_Christensenellaceae and unclassified_f_Ruminococcaceae. In conclusion, a high dosage of UDCA can alleviate liver inflammation, probably by modifying the composition of gut microbiota and serum bile acid profiles in NASH mice. [Display omitted] • A daily dosage of 300 mg/kg of UDCA ameliorates hepatic inflammation in NASH mouse model. • A daily dosage of 300 mg/kg of UDCA remodels gut microbiota composition and changes metabolic function in treating NASH. • Bile acid profile exhibits significant alteration following daily treatment with a dosage of 300 mg/kg of UDCA. • The alteration of bile acid profile following UDCA treatment contributes to the amelioration of the NASH mouse model. [ABSTRACT FROM AUTHOR]

The aim of the study was to explore the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentrations and regional body fat deposition in 2011–2018 National Health and Nutrition Examination Survey participants aged 18 to 59 years. We hypothesized that serum 25(OH)D concentrations were negatively associated with total, appendicular, and truncal fat deposition. Serum 25(OH)D concentration was categorized into sufficient (≥75.0 nM), insufficient (50.0–74.9 nM), and deficient (<50.0 nM) groups. Fat mass (FM) was measured by dual-energy X-ray absorptiometry, and FM index (FMI) was calculated by dividing FM (kg) with height2 (m2). Multivariant linear regression and Granger causal analysis were performed to assess the causal relationship between vitamin D status and regional FMIs. Overall serum 25(OH)D concentrations were negatively associated with total (β = –0.029, standard error [SE] = 0.002), trunk (β = –0.015, SE = 0.001), arms (β = –0.004, SE = 3.09 × 10−4), and legs (β = –0.010, SE = 0.001) FMIs in all participants (P <.001, respectively); however, after stratified by vitamin D status and BMI, the negative associations were only observed in individuals with vitamin D deficiency and obesity. The causal analysis indicated that serum 25(OH)D concentrations may causally reduce the arms (F = 4.917, probability [ P ] = 0.007), legs (F = 5.783, P = 0.003), and total (F = 3.202, P = 0.041) FMIs except for trunk FMI but not vice versa. In conclusion, poor vitamin D status was associated with increased total and appendicular body fat deposition in US adults, particularly in participants with obesity. The aim of the study was to explore the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentrations and body fat deposition in adults. The results showed that poor vitamin D status was associated with increased total and appendicular body fat deposition in US adults, particularly in participants with obesity. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Major depression disorder (MDD) has been associated with increased breast cancer risk in epidemiological studies; however, it is still unknown whether this association is causal or not. The aim of this study is to determine the causal relationship between MDD and breast cancer risk. Methods: Two‐sample Mendelian randomization (MR) analyses with 92 single‐nucleotide polymorphisms (SNPs) significantly associated with MDD as instrumental variables (IVs) were performed. Effects of these SNPs on breast cancer in women were estimated in the Breast Cancer Association Consortium (122,977 cases and 105,974 controls) using inverse variance weighted (IVW), weighted median and multivariable MR models. Heterogeneity and pleiotropy effects were assessed based on IVW and MR‐Egger regression model, respectively. Results: An 8.7% increased risk of overall breast cancer [odds ratio (OR) = 1.087; 95% confidence interval (CI) 1.011–1.170; P = 0.025] per log‐odds ratio increment of MDD risk based on the IVW model was noticed. Similar results were obtained with the multivariable MR model (OR = 1.118, 95% CI = 1.010–1.237; P = 0.031). An increment but not statistically significant causality association was noticed between MDD and risk of ER+ (OR = 1.098, 95% CI = 0.984–1.227; P = 0.093) or ER‐ (OR = 1.129, 95% CI = 0.982–1.297; P = 0.089) breast cancer under multivariable MR model. No significant pleiotropy effects were observed for the IVs in the two‐sample MR studies. Conclusions: The results suggested that a genetic predisposition of MDD is causally associated with overall breast cancer risk; however, the underlying biological mechanisms are worthy of further study. [ABSTRACT FROM AUTHOR]

Purpose: Malignant pleural effusion (MPE) is an adverse prognostic factor in patients with osteoblastic osteosarcoma; however, the cellular contexts of MPE are largely unknown. Experimental design: We performed single‐cell RNA‐sequencing (scRNA‐seq) on 27 260 cells from seven MPE samples and 91 186 cells from eight osteosarcoma tissues, including one recurrent, one lung metastasis and six primary tumour (PT) samples, to characterize their tumour microenvironment. Results: Thirteen main cell groups were identified in osteosarcoma tumour and MPE samples. Immune cells dominate the cellular contexts in MPE with more T/NK cells and less osteoclasts compared to PT samples. Of T/NK cells, CD8+GNLY+, CD8+KLRC2+ T cells and FCGR3A+NK cells were enriched in MPE but CD4+FOXP3+ Tregs were enriched in PT samples. Naïve IGHD+ B and immune regulatory IGHA1+ B cells were largely identified in MPE, whereas bone metabolism‐related CLEC11A+ B cells were significantly enriched in osteosarcoma PT. M2‐type TAMs, including CLEC11A_TAM, C1QC_TAM and Prolif_TAMs, among myeloid cells were enriched in PT, which may suppress cytotoxicity activities of T cells through multiple ligand–receptor interactions. Mature LAMP3+ DCs were transformed from CD1C+ DC and CLEC9A+ DC sub‐clusters when exposure to tumour alloantigens, which may improve T cell cytotoxicity activities on tumour cells under anti‐PD‐L1 treatments. In further, immune cells from MPE usually present up‐regulated glycolysis and down‐regulated oxidative phosphorylation and riboflavin metabolism activities compared to those in PT samples. Conclusions: Our study provided a novel cellular atlas of MPE and PT in patients with advanced osteosarcoma, which may provide potential therapeutic targets in the future. [ABSTRACT FROM AUTHOR]

The vitamin D receptor (VDR) principally mediates the anticancer activities of vitamin D. Various epidemiological studies have investigated the associations of VDR gene polymorphisms with ovarian cancer; however, the results have been inconclusive. In the current study, we evaluated, in a meta-analysis, the association of five common single nucleotide polymorphisms (SNPs) in the VDR gene (ApaI, BsmI, Cdx-2, FokI, and TaqI) with the risk of ovarian cancer. Six eligible studies, with a total of 4,107 cases and 6,661 controls, which evaluated the association of these variants and ovarian cancer risk, were identified from the MEDLINE and PubMed databases. The meta-analysis indicated that FokI was associated with an increased ovarian cancer risk, with a pooled odds ratio (OR) of 1.10 [95% confidence intervals (95% CI) = 1.00–1.20] for CT heterozygotes and 1.16 (95% CI = 1.02–1.30) for TT homozygotes relative to common CC carriers. Carriers of the T allele (also known as the f allele) showed an 11% (pooled OR = 1.11, 95% CI = 1.02–1.21; TT/CT vs. CC) increased risk of ovarian cancer relative to CC carriers. For FokI, no significant heterogeneity between the studies was found (I2 = 0%, P = 0.62 for the Q test). There was no statistically significant association between the other four variants (ApaI, BsmI, Cdx-2 and TaqI) and risk of ovarian cancer. These data indicate that the polymorphism FokI on the VDR is a susceptibility factor for ovarian cancer. Nevertheless, more studies are warranted to elucidate the underlying mechanisms of the VDR in development of ovarian cancer. [ABSTRACT FROM AUTHOR]

Introduction and Aims. Bile acids play an essential role in the progression of nonalcoholic fatty liver disease (NAFLD). This study was aimed at investigating the association of the serum glycocholic acid- (GCA-) to-total bile acid (TBA) ratio with NAFLD in the general population. Materials and Methods. A total of 6708 subjects (2859 cases with NAFLD and 3849 controls) were enrolled in the development cohort and additional 1568 subjects (784 cases with NAFLD and 784 controls) in an independent validation cohort. Demographic characteristics and biochemical data were compared between subjects with NAFLD and controls. Multivariate logistic regression analysis was performed to determine the association of the GCA-to-TBA ratio with NAFLD. A novel model incorporating the GCA-to-TBA ratio was developed for screening NAFLD from the general population. Results. The serum TBA and GCA levels were significantly higher in subjects with NAFLD than in those without NAFLD (2.8 (2.0-4.2) μmol/L vs. 2.5 (1.8-3.7) μmol/L and 1.30 (1.10-1.53) μg/mL vs. 1.28 (1.08-1.50) μg/mL, respectively, all p ≤ 0.01), whereas the serum GCA-to-TBA ratio was significantly lower in subjects with NAFLD than in subjects without NAFLD (0.44 (0.33-0.60) vs. 0.48 (0.36-0.64), p ≤ 0.01). Logistic regression analysis showed that the GCA-to-TBA ratio was independently associated with NAFLD after adjustment for confounding factors (odds ratio: 0.81, 95% confidence interval (CI): 0.71-0.92, p ≤ 0.01). The area under the receiver operating characteristic curve of the novel developed GCA-to-TBA ratio score model in discriminating NAFLD was 0.84 (95% CI: 0.83-0.85) in the development cohort and was 0.91 (95% CI: 0.36-0.65) in the validation cohort. Conclusion. The serum GCA-to-TBA ratio is independently associated with NAFLD. A simple novel model incorporating the GCA-to-TBA ratio score has a good performance in discriminating NAFLD from the general population. [ABSTRACT FROM AUTHOR]

Objectives: Integrin beta‐like 1 (ITGBL1) is involved in the migration and invasion of several cancers; however, its roles in the development and progression of hepatocellular carcinoma (HCC) remain largely unknown. Materials and methods: Immunohistochemistry staining was used to investigate the expression pattern of ITGBL1 and its prognostic values in HCC patients. The transwell, wound‐healing assays, xenograft and orthotopic mouse models were employed to determine the effects of ITGBL1 on HCC cell migration and invasion in vitro and in vivo. The biological mechanisms involved in cell migration and invasion caused by ITGBL1 were determined with Western blotting and RT‐PCR methods. Results: ITGBL1 expression was significantly increased in HCC tissues compared to adjacent normal tissues. Patients with higher ITGBL1 expression were associated with more reduced overall survival. ITGBL1 overexpression promoted migration and invasion in SMMC‐7721 and HepG2 cells in vitro and in vivo, whereas knockdown or knockout ITGBL1 in CSQT‐2 cells significantly reduced cell migration and invasion abilities. In SMMC‐7721 cells, ITGBL1 overexpression stimulated TGF‐β/Smads signalling pathway, along with the KRT17 and genes involved in the epithelial‐mesenchymal transition (EMT). In contrast, ITGBL1 knockout inhibited the TGF‐β/Smads signalling pathway in CSQT‐2 cells. Conclusions: These findings suggested that ITGBL1 promoted migration and invasion in HCC cells by stimulating the TGF‐β/Smads signalling pathway. ITGBL1 could be a promising prognostic biomarker, as well as a potential therapeutic target in HCC. [ABSTRACT FROM AUTHOR]

Patients receiving sorafenib treatment for hepatocellular carcinoma (HCC) experience different treatment efficacy. Personalized sorafenib treatment should be achieved through the identification of predictors of therapeutic response. In the current study, we found that high UGT1A9 expression indicated better prognosis for HCC patients treated with sorafenib after surgery. In silico analysis predicted microRNA-200a/-183 as potential regulators of the UGT1A gene family via binding to the shared UGT1A9 3'-UTR. A significant inverse correlation between microRNA-200a/-183 and UGT1A9 mRNA level was observed in a panel of HCC specimens. Direct binding was further demonstrated by luciferase reporter gene vector carrying wild-type or binding site truncated UGT1A9 3'-UTR. MicroRNA-200a/-183 downregulated UGT1A9 expression in a dose-dependent manner and significantly reduced sorafenib β-D-glucuronide formation in HCC cells. These data indicated that UGT1A9, under epigenetic regulation of microRNA-200a/-183, could predict patients who might benefit from adjuvant sorafenib treatment after surgery. [ABSTRACT FROM AUTHOR]

Aims: The presence of pre-existing hepatitis C virus (HCV) resistance-associated substitutions (RASs) could attenuate viral susceptibility to direct-acting antiviral agents. The aim of this study was to better understand the differences among HCV RASs over time. We compared the prevalence and characteristics of naturally occurring HCV RASs in the NS3, NS5A, and NS5B genes between 2008 and 2016 in Chinese patients chronically infected with HCV genotypes (GT) 1b, 2a, 3a, 3b, and 6a. Methods: HCV RNA was extracted after serum samples were collected from 242 patients at treatment baseline, including 120 samples in 2008 and 122 samples in 2016. Reverse transcription and nested PCR were performed, and the PCR products of the NS3, NS5A, and NS5B regions were sequenced using the Sanger sequencing method. Finally, RASs were identified from the different viral strains. Results: In GT1b, the overall frequency of NS5A RASs in 2016 was significantly higher than that in 2008 (42.0% vs. 18.4%; p = 0.002). Among NS5A RASs, the most frequently detected RAS was Y93H (5.3% in 2008 vs. 15.9% in 2016; p = 0.035), which confers medium- to high-level resistance to the NS5A inhibitors: daclatasvir (DCV), ledipasvir (LDV), ombitasvir (OMV), and elbasvir. The frequency of NS5A L28 (low-level resistance to DCV/LDV/OMV) in 2016 was also higher than that in 2008 (11.6% vs. 1.3%; p = 0.027). In addition, the highest frequency of clinically relevant NS3 RASs was S122G/A/T (69.7% in 2008 and 72.5% in 2016) in HCV GT1b isolates, which had medium-level resistance to simeprevir and asunaprevir, followed by Y56F (7.9% in 2008 and 14.5% in 2016), which confers resistance to paritaprevir. Although NS5B C316N had the highest substitution rate in GT1b (80.2% in 2008 and 91.3% in 2016), it was associated with low-level resistance to sofosbuvir and dasabuvir. However, HCV RASs were rarely detectable at baseline in other genotypes or subtypes except GT1b in this study. Conclusion: The frequency of NS5A RASs in 2016 was significantly higher than that in 2008, especially at the L28 and Y93 substitution positions, which may be due to their better fitness compared with wild-type viruses. [ABSTRACT FROM AUTHOR]

Carbamoyl phosphate synthetase 1 (CPS1), which is the antigen for the hepatocyte paraffin 1 antibody, exhibits focal immunoreactivity in adenocarcinoma from the gastrointestinal tract, but its expression profiles and roles in gastric cancer (GC) remain largely unknown. The present study aimed to determine the expression pattern and prognostic value of CPS1 in Correa's cascade using tissues from 32 patients with chronic atrophic gastritis with intestinal metaplasia (IM), 62 patients with low- or high-grade intraepithelial neoplasia (IN) and 401 patients with GC. The expression of CPS1 was diffuse and strongly positive in 32 cases (100%) of IM of the glandular epithelium, and gradually downregulated in Correa's cascade, with a strongly positive ratio of 21 (70%) in low-grade IN and 4 (12.5%) in high-grade IN. The levels of CPS1 expression were significantly higher in diffuse-type GC, with 37 (26%) cases strongly positive for CPS1, compared with 14 (8%) in intestinal-type and 11 (13%) cases in mixed-type GC. In intestinal-type GC, CPS1 expression was completely lost in 107 (62%) of cases, which was associated with an advanced Tumor-Node-Metastasis stage (P=0.031) and depth of invasion (P=0.037). Kaplan-Meier analysis suggested that low CPS1 expression levels were independently associated with a short overall survival (OS) time in the three types of GC (P<0.001 in intestinal-type, P=0.003 in diffuse-type and P=0.018 in mixed-type GC). Furthermore, low levels of CPS1 mRNA and high methylation levels in the CPS1 promoter were associated with a short OS time in patients with GC. These results suggested that the expression of CPS1 was progressively downregulated in Correa's cascade, and that CPS1 may serve as a prognostic marker for patients with GC, regardless of tumor type. [ABSTRACT FROM AUTHOR]

Background: Although metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide, the exact molecular mechanism of MAFLD progression remains unknown. In the present study, Tandem Mass Tag-labeled quantitative proteomic technology was used to elucidate the protein expression patterns of liver tissues in the progression of MAFLD, providing new potential therapeutic targets of it. Methods: Five 6-week-old male C57BL/6 mice were fed with high fat diet (HFD) for 22 weeks to establish the MAFLD mouse models. Five C57BL/6 mice of the same age were fed with normal diet (ND) and taken as controls. Mice serum were sampled for biochemical tests, and livers were isolated for histopathological examinations. Six mouse liver samples (three from each group) were performed for proteomic analysis. Differentially expressed proteins were defined using fold change of > 1.5 or < 0.67 and p value < 0.05 as thresholds. Bioinformatic analysis was used to identify the hub proteins. Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), Gene Expression Omnibus dataset, western blotting and immunohistochemistry were used to validate the expression of identified hub proteins. Results: After 22 weeks on HFD diet, all mice developed MAFLD demonstrated by histopathological examination. Mouse body weights, liver weights, serum alanine transaminase and aspartate transaminase levels were significantly higher in the HFD group than ND group. Proteomics technology identified 4915 proteins in the mouse livers, among which 71 proteins were differentially expressed. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that majority of the differentially expressed proteins were involved in the peroxisome and peroxisome proliferator-activated receptor signaling pathway, as well as biosynthesis of unsaturated fatty acids. Protein–protein interaction analysis showed that these differentially expressed proteins interacted with each other and formed a complex network. Ten hub proteins were identified and validated using RT-qPCR. Five of these proteins were validated in the Gene Expression Omnibus dataset. Finally, Enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase protein was validated in mouse liver tissue samples using western blotting and immunohistochemistry. Conclusion: Our data showed that lipid metabolism-related pathways are closely associated with the development of MAFLD. The identified hub proteins might be novel targets for treating MAFLD. [ABSTRACT FROM AUTHOR]

Although hepatitis B virus (HBV) infection is the leading cause of liver fibrosis (LF), the mechanisms underlying liver fibrotic progression remain unclear. Here, we investigated the gene expression profiles of HBV-related LF patients. Whole genome expression arrays were used to detect gene expression in liver biopsy samples from chronically HBV infected patients. Through integrative data analysis, we identified several pathways and key genes involved in the initiation and exacerbation of liver fibrosis. Weight gene co-expression analysis revealed that integrin subunit β-like 1 (ITGBL1) was a key regulator of fibrogenesis. Functional experiments demonstrated that ITGBL1 was an upstream regulator of LF via interactions with transforming growth factor β1. In summary, we investigated the gene expression profiles of HBV-related LF patients and identified a key regulator ITGBL1. Our findings provide a foundation for future studies of gene functions and promote the development of novel antifibrotic therapies. [ABSTRACT FROM AUTHOR]