LncRNA H19 promoted alcohol-associated liver disease through dysregulation of alternative splicing and methionine metabolism.

BACKGROUND AND AIMS: Long noncoding RNAs constitute a significant portion of the human genome. Among these, lncRNA H19, initially identified for its high expression during fetal development followed by a decline in the liver postnatally, re-emerges in various liver diseases. However, its specific role in alcohol-associated liver disease (ALD) remains unclear. APPROACH AND RESULTS: Elevated H19 levels were detected in peripheral blood and livers of patients with alcohol-associated cirrhosis and hepatitis, as well as in livers of ethanol-fed mice. Hepatic overexpression of H19 exacerbated ethanol-induced liver steatosis and injury. Metabolomics analysis revealed decreased methionine levels in H19-overexpressed mouse livers, attributable to H19-mediated inhibition of betaine homocysteine methyltransferase (BHMT), a crucial enzyme in methionine synthesis. H19 regulated BHMT alternative splicing through polypyrimidine tract-binding protein 1 (PTBP1), resulting in a reduced Bhmt protein-coding variant. The maternally specific knockout of H19 (H19Mat+/-) or liver-specific knockout of the H19 differentially methylated domain (H19DMDHep-/-) in ethanol-fed mice upregulated BHMT expression and ameliorated hepatic steatosis. Furthermore, BHMT restoration counteracted H19-induced ethanol-mediated hepatic steatosis. CONCLUSIONS: This study identifies a novel mechanism whereby H19, via PTBP1-mediated BHMT regulation, influences methionine metabolism in ALD. Targeting the H19-PTBP1-BHMT pathway may offer new therapeutic avenues for ALD.

Understanding vermicompost and organic manure interactions: impact on toxic elements, nitrification activity, comammox Nitrospira inopinata, and archaea/bacteria.

Vermicompost is a substantial source of nutrients, promotes soil fertility, and maintains or increases soil organic matter levels. Potentially toxic elements (PTEs) in vermicompost impact on nitrification activity. However, it is yet unknown how vermicompost affects nitrifying bacteria and archaea, comammox Nitrospira inopinata (complete ammonia oxidizers), net nitrification rates (NNRs), and PTEs. The effects of vermicompost application on NNRs, potential nitrification rates (NPs), PTEs, and the abundances of comammox N. inopinata bacteria, nitrite-oxidizing bacteria (NOB), and ammonia-oxidizing bacteria (AOB)/archaea (AOA) were studied. NNRs and NPs were significantly higher (p < 0.05) in fresh cow-dung vermicompost (stored for 40 days) as compared with other organic manure. The level of PTEs (Cu2+, Fe2+, Pb2+, Cd2+, and Zn2+) was significantly lower (p < 0.05) in vermicompost as compared with compost of waste material with Trichoderma and cow dung. Comammox N. inopinata, NOB, AOB, and AOA were significantly higher (p < 0.05) in stored cow-dung vermicompost (more than 1 year) as compared with other organic manure. The results of the scatterplot matrix analysis suggested that Fe2+, total nitrogen (TN), soil organic carbon (SOC), and total carbon (TC) were linearly correlated (p < 0.001) with NNRs and NPs in vermicompost and organic manure. Similarly, comammox N. inopinata bacteria, NOB, AOB, and AOA were linearly correlated (p < 0.001) with NNR and NP. These results indicated that vermicompost promoted nitrification activity by increasing microbial diversity and abundance, supplying nutrients and organic matter for microbial growth, and facilitating complex microbial interactions. It may be concluded that the influence of vermicompost, which played a great role in PTE concentration reduction, increased chemical, and biological properties, increased the growth rate of nitrifying bacteria/archaea and the nitrogen cycle.

Transcriptomic Analysis Reveals the MicroRNAs Responsible for Liver Regeneration Associated With Mortality in Alcohol-Associated Hepatitis.

BACKGROUND AND AIMS: We conducted a comprehensive serum transcriptomic analysis to explore the roles of microRNAs (miRNAs) in alcohol-associated hepatitis (AH) pathogenesis and their prognostic significance. APPROACH AND RESULTS: Serum miRNA profiling was performed in 15 controls, 20 heavy drinkers without liver disease, and 65 patients with AH and compared to publicly available hepatic miRNA profiling in AH patients. Among the top 26 miRNAs, expression of miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p were significantly reduced in both serum and liver of AH patients. Pathway analysis of the potential targets of these miRNAs uncovered the genes related to DNA synthesis and cell-cycle progression pathways, including ribonucleotide reductase regulatory subunit M2 (RRM2), cyclin D1 (CCND1), cyclin D2 (CCND2), MYC proto-oncogene (MYC), and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1). We found a significant increase in the protein expression of RRM2, CCND1, and CCND2, but not MYC and PMAIP1, in AH patients who underwent liver transplantation; miR-26b-5p and miR-30b-5p inhibited the 3'-UTR (untranslated region) luciferase activity of RRM2 and CCND2, and miR-20a-5p reduced the 3'-UTR luciferase activity of CCND1 and CCND2. During a median follow-up of 346 days, 21% of AH patients died; these patients had higher body mass index (BMI), Model for End-Stage Liver Disease (MELD), and serum miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p than those who survived. Cox regression analysis showed that BMI, MELD score, miR-20a-5p, miR-146a-5p, and miR-26b-5p predicted mortality. CONCLUSIONS: Patients with AH attempt to deal with hepatocyte injury by down-regulating specific miRNAs and up-regulating genes responsible for DNA synthesis and cell-cycle progression. Higher expression of these miRNAs, suggestive of a diminished capacity in liver regeneration, predicts short-term mortality in AH patients.

Stress-Responsive Gene FK506-Binding Protein 51 Mediates Alcohol-Induced Liver Injury Through the Hippo Pathway and Chemokine (C-X-C Motif) Ligand 1 Signaling.

BACKGROUND AND AIMS: Chronic alcohol drinking is a major risk factor for alcohol-associated liver disease (ALD). FK506-binding protein 51 (FKBP5), a cochaperone protein, is involved in many key regulatory pathways. It is known to be involved in stress-related disorders, but there are no reports regarding its role in ALD. This present study aimed to examine the molecular mechanism of FKBP5 in ALD. APPROACH AND RESULTS: We found a significant increase in hepatic FKBP5 transcripts and protein expression in patients with ALD and mice fed with chronic-plus-single binge ethanol. Loss of Fkbp5 in mice protected against alcohol-induced hepatic steatosis and inflammation. Transcriptomic analysis revealed a significant reduction of Transcriptional enhancer factor TEF-1 (TEA) domain transcription factor 1 (Tead1) and chemokine (C-X-C motif) ligand 1 (Cxcl1) mRNA in ethanol-fed Fkbp5-/- mice. Ethanol-induced Fkbp5 expression was secondary to down-regulation of methylation level at its 5' untranslated promoter region. The increase in Fkbp5 expression led to induction in transcription factor TEAD1 through Hippo signaling pathway. Fkbp5 can interact with yes-associated protein (YAP) upstream kinase, mammalian Ste20-like kinase 1 (MST1), affecting its ability to phosphorylate YAP and the inhibitory effect of hepatic YAP phosphorylation by ethanol leading to YAP nuclear translocation and TEAD1 activation. Activation of TEAD1 led to increased expression of its target, CXCL1, a chemokine-mediated neutrophil recruitment, causing hepatic inflammation and neutrophil infiltration in our mouse model. CONCLUSIONS: We identified an FKBP5-YAP-TEAD1-CXCL1 axis in the pathogenesis of ALD. Loss of FKBP5 ameliorates alcohol-induced liver injury through the Hippo pathway and CXCL1 signaling, suggesting its potential role as a target for the treatment of ALD.

Biosynthesis and chemical composition of nanomaterials in agricultural soil bioremediation: a review.

Nanomaterials (NMs) are currently being used in agricultural soils as part of a new bioremediation (BR) process. In this study, we reviewed the biosynthesis of NMs, as well as their chemical composition and prospective strategies for helpful and sustainable agricultural soil bioremediation (BR). Different types of NMs, such as nanoparticles, nanocomposites, nanocrystals, nano-powders, and nanotubes, are used in agricultural soil reclamation, and they reflect the toxicity of NMs to microorganisms. Plants (Sargassum muticum, Dodonaea viscose, Aloe Vera, Rosemarinus officinalis, Azadirachta indica, Green tea, and so on) and microorganisms (Escherichia coli, Shewanella oneidensis, Pleurotus sp., Klebsiella oxytoca, Aspergillus clavatus, and so on) are the primary sources for the biosynthesis of NMs. By using the BR process, microorganisms, such as bacteria and plants, can immobilize metals and change both inorganic and organic contaminants in the soil. Combining NMs with bioremediation techniques for agricultural soil remediation will be a valuable long-term solution.

What drives WEEE recycling? A comparative study concerning legislation, collection and recycling.

Waste electrical and electronic equipment (WEEE) has been rising worldwide, and its improper management incurs in economic losses and environmental damage. To provide a better understanding of the forces that drive the management of WEEE, economic and political roles are discussed by comparing the WEEE recycling system of Brazil and Australia. Additional insights about the recycling systems were gathered from interviews with recyclers of both countries (in-loco visits and online/phone surveys). Previous studies show that both countries act as first stage recyclers, dismantling WEEE to ship their valuable components for international recyclers (such as printed circuit boards) while keeping less valuable material (such as polymeric and ferrous pieces). Australia has defined the responsibilities of most agents involved in the WEEE management and recycling setup, while Brazil inadvertently has left the system to be defined through free market regulation. As Brazil recently signed a reverse logistic agreement, there is an important opportunity to channel WEEE into formal routes and implement improvements in the entire recycling system (some suggestions are provided). Australian recyclers were found more organised in their disassembly lines, and some characteristics of the Australian model can be adapted for the Brazilian benefit. In conclusion, economic factors will drive first stage recycling (where labour wages are a small fraction of the total costs) and international downstream recycling, while a political framework is necessary to establish a comprehensive collection system, first stage recycling (where wages are representative) and domestic downstream recycling, given these are generally non-profitable activities in the short term.

Reverse logistics network design for waste solar photovoltaic panels: A case study of New South Wales councils in Australia.

Waste solar photovoltaic (PV) panels are considered as one of the fastest-growing future waste streams under the category of large electronic waste (e-waste). The lifespan of solar panels varies from 20 to 30 years, and an appropriate reverse logistics network design is essential to manage the waste stream efficiently once their lifetime expires. Mixed-integer programming-based RL model is proposed in this paper for New South Wales, Australia that minimizes the overall cost by identifying optimal locations and sizing of the collection points while determining optimal capacities for recycling facilities. Using the historical data (2001-2017) on the installed capacity of solar panels in the state, the potential waste generation (at council-level) is estimated and optimized solutions are proposed for the year 2047. The results of the study show that the highest waste solar PV will be generated at Murrumbidgee, Berrigan, Balranald, and Bogan councils. Out of 129 councils in the state, the model identifies 78 optimized-locations of the collection points that would be required in the councils. In the councils of Newcastle, Narrandera and Wagga Wagga, three major recycling facilities would need to be established. This is the first systematic attempt in designing an optimized RL network in Australia focusing on waste solar PV. Policy-makers will find this research highly valuable in decision-making on local recycling infrastructure development.

Waste mobile phones: A survey and analysis of the awareness, consumption and disposal behavior of consumers in Australia.

Electronic waste (e-waste) is one of the fastest-growing waste streams in the world and waste mobile phone (WMP) represents a significant portion of the stream. Consumer awareness, consumption, and disposal behavior are of importance to assist in the implementation the circular economy. In Australia, some 94% of the adult population has a mobile phone, and the only WMP collection and recycling program in the country - "MobileMuster" is operating under a voluntary scheme. This study reveals consumers' familiarity with the program, current consumption, and disposal behavior concerning mobile phones from a survey implemented in Sydney, Australia. In addition to descriptive analysis, statistical analysis (with the Chi-square test of independence and Multinomial Logistic Regression (MLR)) identifies factors that influenced the behaviors. The results show that only one-third of the respondents (32.42%) were aware of the program, and that there are 3.65 mobile phones in use per household, with an average possession lifespan of 3.17 years (including storage). Furthermore, there is a positive relationship between age and possession of mobile phones, and respondents discard or change their mobile phones while they were still working or repairable. The main reasons for disposing of mobile phones relate to them being either damaged/not functioning, lacking additional features, or having a backdated capacity. Storing (hoarding) mobile phones after active use was found predominant, and, more specifically, respondents aged 18-24 and 25-29 preferred to store their WMPs instead of taking them to collection points. The results reveal a need for environmental awareness-raising campaigns concerning WMPs recycling.

Role of High-Mobility Group Box-1 in Liver Pathogenesis.

High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases.

Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions.

Alcohol-related liver disease (ALD) is caused by over-consumption of alcohol. ALD can develop a spectrum of pathological changes in the liver, including steatosis, inflammation, cirrhosis, and complications. Autophagy is critical to maintain liver homeostasis, but dysfunction of autophagy has been observed in ALD. Generally, autophagy is considered to protect the liver from alcohol-induced injury and steatosis. In this review, we will summarize novel modulators of autophagy in hepatic metabolism and ALD, including autophagy-mediating non-coding RNAs (ncRNAs), and crosstalk of autophagy machinery and nuclear factors. We will also discuss novel functions of autophagy in hepatocytes and non-parenchymal hepatic cells during the pathogenesis of ALD and other liver diseases.

Material flow analysis (MFA) as a strategic tool in E-waste management: Applications, trends and future directions.

Material flow analysis (MFA) is one of the most widely accepted and utilized tools in the industrial-ecology discipline, that measures the input-output materials and examines the pathways and flux of each material flow within the whole system. The application of MFA in e-waste management has recently increased and quite a few academic articles have been published on this issue providing decision support at the policy level. However, there is a need to understand the dynamics of MFA methodology, the data requirements (as well as the data sources used in the previous studies) and the lessons learnt from the studies, so that countries where such an E-waste-MFA study has not yet been performed can apply the international experience of such an emerging research technique. This comprehensive review article presents the recent applications, trends, characteristics, research gaps and challenges of the MFA method that may help e-waste management with an overview of the need for a such tool to be applied. A country-wise analysis is presented and MFA models complemented by various associated methods are summarized with national-level, regional-level, product-level, and element-level assessment. The highlighted future research perspectives discussed in this study will help to analyze e-waste management systems more critically, including the hidden and known flows of waste products and associated materials, economic assessment of material recovery and the role of responsible authorities. This invaluable contribution will help future researchers, particularly from the data collection techniques and previously applied MFA models complemented by various associated methods.

Homeostatic Role of Autophagy in Hepatocytes.

Autophagy actively participates in the physiological process of the liver. While the direct effect of autophagy may be limited to the sequestration and degradation of a selective cargo, its overall impact can be broad, affecting many more physiological processes regulated by the particular cargo. This review will discuss two aspects of the importance of autophagy in the liver: metabolic regulation in response to feeding and starvation, and pathological consequences in the absence of autophagy. These two aspects illustrate the homeostatic functions of autophagy in the liver, one in a more direct fashion, regulating the cellular nutrient supply, and the other in a more indirect fashion, controlling the pathological signaling triggered by the abnormal accumulation of cargos. Remarkably, the hepatic pathology in autophagy-deficient livers does not seem different from that presented in other chronic liver diseases. Autophagy deficiency can be a model for the study of the relevant molecular mechanisms.

Relevance of autophagy to fatty liver diseases and potential therapeutic applications.

Autophagy is an evolutionarily conserved lysosome-mediated cellular degradation program. Accumulating evidence shows that autophagy is important to the maintenance of liver homeostasis. Autophagy involves recycling of cellular nutrients recycling as well as quality control of subcellular organelles. Autophagy deficiency in the liver causes various liver pathologies. Fatty liver disease (FLD) is characterized by the accumulation of lipids in hepatocytes and the dysfunction in energy metabolism. Autophagy is negatively affected by the pathogenesis of FLD and the activation of autophagy could ameliorate steatosis, which suggests a potential therapeutic approach to FLD. In this review, we will discuss autophagy and its relevance to liver diseases, especially FLD. In addition, we will discuss recent findings on potential therapeutic applications of autophagy modulators for FLD.

Widespread telomere instability in prostatic lesions.

A critical function of the telomere is to disguise chromosome ends from cellular recognition as double strand breaks, thereby preventing aberrant chromosome fusion events. Such chromosome end-to-end fusions are known to initiate genomic instability via breakage-fusion-bridge cycles. Telomere dysfunction and other forms of genomic assault likely result in misregulation of genes involved in growth control, cell death, and senescence pathways, lowering the threshold to malignancy and likely drive disease progression. Shortened telomeres and anaphase bridges have been reported in a wide variety of early precursor and malignant cancer lesions including those of the prostate. These findings are being extended using methods for the analysis of telomere fusions (decisive genetic markers for telomere dysfunction) specifically within human tissue DNA. Here we report that benign prostatic hyperplasia (BPH), high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer (PCa) prostate lesions all contain similarly high frequencies of telomere fusions and anaphase bridges. Tumor-adjacent, histologically normal prostate tissue generally did not contain telomere fusions or anaphase bridges as compared to matched PCa tissues. However, we found relatively high levels of telomerase activity in this histologically normal tumor-adjacent tissue that was reduced but closely correlated with telomerase levels in corresponding PCa samples. Thus, we present evidence of high levels of telomere dysfunction in BPH, an established early precursor (PIN) and prostate cancer lesions but not generally in tumor adjacent normal tissue. Our results suggest that telomere dysfunction may be a common gateway event leading to genomic instability in prostate tumorigenesis. .

Telomere fusions in early human breast carcinoma.

Several lines of evidence suggest that defects in telomere maintenance play a significant role in the initiation of genomic instability during carcinogenesis. Although the general concept of defective telomere maintenance initiating genomic instability has been acknowledged, there remains a critical gap in the direct evidence of telomere dysfunction in human solid tumors. To address this topic, we devised a multiplex PCR-based assay, termed TAR (telomere-associated repeat) fusion PCR, to detect and analyze chromosome end-to-end associations (telomere fusions) within human breast tumor tissue. Using TAR fusion PCR, we found that human breast lesions, but not normal breast tissues from healthy volunteers, contained telomere fusions. Telomere fusions were detected at similar frequencies during early ductal carcinoma in situ and in the later invasive ductal carcinoma stage. Our results provide direct evidence that telomere fusions are present in human breast tumor tissue and suggest that telomere dysfunction may be an important component of the genomic instability observed in this cancer. Development of this robust method that allows identification of these genetic aberrations (telomere fusions) is anticipated to be a valuable tool for dissecting mechanisms of telomere dysfunction.

Elevated levels of plasma uric acid and its relation to hypertension in arsenic-endemic human individuals in Bangladesh.

Blood uric acid has been recognized as a putative marker for cardiovascular diseases (CVDs). CVDs are the major causes of arsenic-related morbidity and mortality. However, the association of arsenic exposure with plasma uric acid (PUA) levels in relation to CVDs has not yet been explored. This study for the first time demonstrated the associations of arsenic exposure with PUA levels and its relationship with hypertension. A total of 483 subjects, 322 from arsenic-endemic and 161 from non-endemic areas in Bangladesh were recruited as study subjects. Arsenic concentrations in the drinking water, hair and nails of the study subjects were measured by inductively coupled plasma mass spectroscopy. PUA levels were measured using a colorimetric method. We found that PUA levels were significantly (p<0.001) higher in males and females living in arsenic-endemic areas than those in non-endemic area. Arsenic exposure (water, hair and nail arsenic) levels showed significant positive correlations with PUA levels. In multiple regression analyses, arsenic exposure levels were found to be the most significant contributors on PUA levels among the other variables that included age, body mass index, blood urea nitrogen, and smoking. There were dose-response relationships between arsenic exposure and PUA levels. Furthermore, diastolic and systolic blood pressure showed significant positive correlations with PUA levels. Finally, the average PUA levels were significantly higher in the hypertensive group than those in the normotensive group in both males and females living in arsenic-endemic areas. These results suggest that arsenic exposure-related elevation of PUA levels may be implicated in arsenic-induced CVDs.

Optimise inlet condition and design parameters of a new sewer overflow screening device using numerical model.

After heavy rainfall, sewer overflow spills to receiving water bodies cause serious concern for the environment, aesthetics and public health. To overcome these problems this study investigated a new self-cleansing sewer overflow screening device. The device has a sewer overflow chamber, a rectangular tank and a slotted ogee weir to capture the gross pollutants. To design an efficient screening device a numerical computational fluid dynamic (CFD) model was used. A plausibility check of the CFD model was done using a one-dimensional analytical model. Results showed that an inlet parallel to the weir ensured better self-cleansing than an inlet perpendicular to the weir. Perforations should be at the bottom of the weir to get increased velocity and shear stress to create a favourable self-cleaning effect of the screening device. Increasing inlet length from 0.3 to 1.5 m reduced wave reflection up to 10%, which increased flow uniformity downstream and improved self-cleansing effect. The orientation of the ogee weir with the rectangular tank was found most uniform with a 1:3 (horizontal:vertical) slope. These results will help to maximise functional efficiency of the new sewer overflow screening device. Otherwise it would be too expensive to alter after installation and at times difficult to customise accordingly to existing urban drainage systems.

FK-binding protein 5: Possible relevance to the pathogenesis of metabolic dysfunction and alcohol-associated liver disease.

The FK506-binding protein (FKBP5) plays significant roles in mediating stress responses by interacting with glucocorticoids, participating in adipogenesis, and influencing various cellular pathways throughout the body. In this review, we described the potential role of FKBP5 in the pathogenesis of two common chronic liver diseases, metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol-associated liver disease (ALD). We provided an overview of the FK-binding protein family and elucidated their roles in cellular stress responses, metabolic diseases, and adipogenesis. We explored how FKBP5 may mechanistically influence the pathogenesis of MASLD and ALD and provided insights for further investigation into the role of FKBP5 in these two diseases.

Unique urine and serum metabolomic signature in patients with excessive alcohol use: An exploratory study.

BACKGROUND: Excessive alcohol consumption has a multifaceted impact on the body's metabolic pathways and organ systems. The objectives of this study were to characterize global metabolomic changes and identify specific pathways that are altered in individuals with excessive alcohol use. METHODS: This exploratory study included 22 healthy controls with no known history of excessive alcohol use and 38 patients identified as using alcohol excessively. A Fibrosis-4 score was used to determine the risk of underlying alcohol-associated liver disease among the excessive drinkers. RESULTS: We found significantly altered urinary and serum metabolites among excessive drinkers, affecting various metabolic pathways including the metabolism of lipids, amino acids and peptides, cofactors and vitamins, carbohydrates, and nucleotides. Levels of two steroid hormones-5alpha-androstan-3beta,17beta-diol disulfate and androstenediol (3beta,17beta) disulfate-were significantly higher in both the serum and urine samples of excessive drinkers. These elevated levels may be associated with a higher risk of liver fibrosis in individuals with excessive alcohol use. CONCLUSION: Alcohol consumption leads to marked alterations in multiple metabolic pathways, highlighting the systemic impact of alcohol on various tissues and organ systems. These findings provide a foundation for future mechanistic studies aimed at elucidating alcohol-induced changes in these metabolic pathways and their implications.

HMGB2 is a potential diagnostic marker and therapeutic target for liver fibrosis and cirrhosis.

BACKGROUND: High mobility group proteins 1 and 2 (HMGB1 and HMGB2) are 80% conserved in amino acid sequence. The function of HMGB1 in inflammation and fibrosis has been extensively characterized. However, an unaddressed central question is the role of HMGB2 on liver fibrosis. In this study, we provided convincing evidence that the HMGB2 expression was significantly upregulated in human liver fibrosis and cirrhosis, as well as in several mouse liver fibrosis models. METHODS: The carbon tetrachloride (CCl4) induced liver fibrosis mouse model was used. AAV8-Hmgb2 was utilized to overexpress Hmgb2 in the liver, while Hmgb2-/- mice were used for loss of function experiments. The HMGB2 inhibitor inflachromene and liposome-shHMGB2 (lipo-shHMGB2) were employed for therapeutic intervention. RESULTS: The serum HMGB2 levels were also markedly elevated in patients with liver fibrosis and cirrhosis. Deletion of Hmgb2 in Hmgb2-/- mice or inhibition of HMGB2 in mice using a small molecule ICM slowed the progression of CCl4-induced liver fibrosis despite constant HMGB1 expression. In contrast, AAV8-mediated overexpression of Hmgb2 enchanced CCl4-incuded liver fibrosis. Primary hepatic stellate cells (HSCs) isolated from Hmgb2-/- mice showed significantly impaired transdifferentiation and diminished activation of α-SMA, despite a modest induction of HMGB1 protein. RNA-seq analysis revealed the induction of top 45 CCl4-activated genes in multiple signaling pathways including integrin signaling and inflammation. The activation of these genes by CCl4 were abolished in Hmgb2-/- mice or in ICM-treated mice. These included C-X3-C motif chemokine receptor 1 (Cx3cr1) associated with inflammation, cyclin B (Ccnb) associated with cell cycle, DNA topoisomerase 2-alpha (Top2a) associated with intracellular component, and fibrillin (Fbn) and fibromodulin (Fmod) associated with extracellular matrix. CONCLUSION: We conclude that HMGB2 is indispensable for stellate cell activation. Therefore, HMGB2 may serve as a potential therapeutic target to prevent HSC activation during chronic liver injury. The blood HMGB2 level may also serve as a potential diagnostic marker to detect early stage of liver fibrosis and cirrhosis in humans.