Chronic viral hepatitis caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) remains a leading global public health burden, driving progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) through complex interactions between viral replication, host immune responses, and extracellular matrix (ECM) remodelling. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that serve as central regulators of ECM homoeostasis and immune modulation in the liver. While physiological MMP activity is essential for tissue repair and immune surveillance, dysregulation of the MMP/TIMP (tissue inhibitors of metalloproteinases) axis during viral hepatitis promotes hepatic fibrogenesis, immune evasion, and malignant transformation, positioning MMPs as both drivers of disease progression and promising therapeutic targets. This review comprehensively examines the molecular and cellular mechanisms governing MMP/TIMP dysregulation across the spectrum of viral hepatitis, with particular focus on HCV and HBV. We address the reciprocal interactions between these viruses and MMP/TIMP expression, the roles of MMPs in liver fibrosis, viral replication, hepatocarcinogenesis, and immunomodulation of the tumour microenvironment, and the accelerated fibrogenic mechanisms in HIV-HCV and HIV-HBV coinfection. The review also extends to acute viral hepatitis (HAV and HEV), where direct MMP/TIMP data remain scarce but mechanistic and indirect ECM evidence indicate significant involvement. Finally, we critically evaluate current and emerging MMP-targeted therapeutic strategies including selective inhibitors, nanoparticle delivery systems, and RNA-based approaches and highlight key unresolved questions to guide future research towards disease-tailored interventions against viral hepatitis-driven liver damage and malignant progression.

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are characterized by disrupted bile acid (BA) homeostasis and subsequent liver injury. Emerging evidence indicates that circadian rhythms significantly influence liver metabolism and the pathogenesis of liver diseases. CD36 has been identified as a regulator of the hepatic circadian clock and metabolic processes; however, the specific mechanisms by which CD36 links circadian rhythms to cholestatic liver disease remain unclear. In this study, we employed bile duct ligation (BDL) mice and liver-specific CD36 knockout (CD36 LKO) mice to examine the role of CD36 in BA metabolism and circadian gene expression. BDL mice presented disrupted rhythms in both liver clock and BA metabolism, accompanied by increased diurnal expression of CD36. Conversely, in the context of BDL, CD36 LKO reduced cholestatic liver injury, improved BA metabolism, and restored diurnal variation of BA levels. Transcriptomic analysis revealed that BA metabolism genes were regulated by CD36, particularly those involved in synthesis, which displayed diurnal variation. Targeted inhibition of CD36 expression effectively mitigated liver injury and inflammation in BDL mice by restoring the rhythmicity of HMGCR/CYP7A1 and normalizing the BA pool size. These findings suggest that CD36 plays a pro-cholestatic role through its regulation of rhythmic BA synthesis and that its inhibition may represent a promising therapeutic strategy for cholestatic liver diseases.

Hypothermic machine perfusion attenuates DCD liver ischemia reperfusion injury via the YAP1/P53-mediated micromitophagy pathway.

A dual-channel fluorescent probe for monitoring hydrogen sulfide and glutathione in alcoholic liver disease and inflammation models

Liver cancer has a high incidence and poor prognosis. Curcumin is a natural compound with anti-tumor activity, but its effects on the STAT3 signaling pathway and the bile acid enterohepatic circulation in liver cancer models remain unclear. To investigate the effects of curcumin on the STAT3 signaling pathway and bile acid enterohepatic circulation in a mouse model of liver cancer. A liver cancer model was established in C57BL/6J mice, which were divided into a sham surgery group, a model control group, low-, medium- and high-dose curcumin groups, a STAT3 inhibitor group, a combination intervention group and a cisplatin positive control group. HE staining was used to observe the pathological morphology of liver tissue. Serum biochemical indicators and IL-6 and TGF-β1 levels were measured. STAT3 pathway proteins were detected by Western blot and related gene expression was analyzed by qRT-PCR. Curcumin dose-dependently inhibited STAT3 signaling activity and reduced the p-STAT3/total STAT3 ratio (P<0.05). In the high-dose curcumin group, serum ALT, AST and TB levels decreased from (254.55±56.14)U/L, (542.01±71.28)U/L and (42.98±8.21)μmol/L to (47.98±10.68)U/L, (135.24±24.12)U/L and (7.91±1.36)μmol/L, respectively (all P<0.05). Curcumin upregulated the expression of BSEP, NTCP and FXR, downregulated Cyp7a1 and upregulated the expression of intestinal Fgf15 and Asbt. Curcumin alleviates liver injury and inflammation while ameliorating bile acid enterohepatic circulation by inhibiting the STAT3 signaling pathway.

Danggui-Shaoyao-San ameliorates metabolic dysfunction-associated steatohepatitis via suppressing hepatic macrophage NLRP3 inflammasome.

Liver ischemia-reperfusion injury (IRI) is a sterile inflammatory process that contributes significantly to graft rejection following liver transplantation. Although SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is known to preserve genomic stability and restrain inflammation under oxidative stress, its immunoregulatory function in myeloid cells during liver IRI has not been elucidated. This study aimed to investigate the role and mechanism of SETDB1 in regulating macrophage-driven inflammatory responses in liver IRI. Myeloid-specific SETDB1 knockout (SETDB1 cKO) mice exhibited exacerbated liver injury, increased infiltration of pro-inflammatory macrophages and neutrophils, and amplified inflammatory responses compared with SETDB1fl/fl controls. Depletion of macrophages alleviated liver damage, reduced neutrophil infiltration and hepatocyte apoptosis, and eliminated the excessive injury observed in SETDB1 cKO mice. Mechanistically, SETDB1 suppressed the expression of purinergic receptor P2X7 (P2RX7). Pharmacological inhibition of P2RX7 with oxidized adenosine triphosphate significantly attenuated liver injury and macrophage infiltration in SETDB1 cKO mice. In vitro assays confirmed that SETDB1 inhibited the P2RX7/Caspase-1/Gasdermin D (GSDMD) pathway in macrophages, thereby limiting pyroptosis and inflammation. This study identifies SETDB1 as a previously unrecognized regulator of macrophage pyroptosis during liver IRI. By linking epigenetic regulation to suppression of the P2RX7/Caspase-1/GSDMD pathway, our findings provide novel mechanistic insight into how SETDB1 protects against sterile liver inflammation. SETDB1 plays a pivotal role in protecting the liver from IRI by restraining macrophage-mediated pyroptosis and inflammation. These findings suggest that targeting the SETDB1/P2RX7/Caspase-1/GSDMD axis may represent a promising therapeutic strategy for mitigating liver IRI and improving transplant outcomes. Antioxid. Redox Signal. 45, 133-148.

Rheumatoid factor (RF) autoantibodies are highly prevalent, yet the molecular determinants of RF development and its progression to rheumatoid arthritis (RA) remain poorly understood. Here, we define the genetic, phenotypic, and molecular architecture of RF and its progression to RA. 469,036 UK Biobank participants with RF testing and 76 ALTRA cohort individuals were studied. Phenome-wide (PheWAS), genome-wide (GWAS), and proteome-wide association studies compared RF-positive individuals without autoimmune disease to RF-negative controls. Single-cell RNA sequencing enabled pseudobulk differential expression and cytokine signature enrichment analyses. RF seroprevalence was 9.3% and longitudinally stable in 94.5% of individuals. PheWAS identified 48 significant associations, led by chronic viral hepatitis (OR 4.8), hypersensitivity pneumonitis (OR 3.6), bronchiectasis (OR 1.9), and COPD (OR 1.4). GWAS of 24,216 RF-positive individuals revealed 29 independent loci; the strongest signal was in the extended HLA region (OR 1.45, P-value=5.4×10-221). Non-HLA loci converged on B cell homeostasis genes (ETS1, BACH2, PAX5, TNFRSF13B, FCGR2A). RF-positive individuals did not carry elevated RA polygenic risk. Proteomic profiling identified 153 differentially abundant proteins enriched for humoral immunity and interferon-induced chemokines, with 79% showing dose-response relationships across titers. Progression to RA involved a shift toward activating tissue-damaging inflammatory pathways rather than amplification of the RF signature. Single-cell transcriptomics of RF-positive individuals without RA localized dysregulation to memory B cells, with downregulation of inhibitory genes (FCGR2B, BACH2, FOXP1) and upregulation of activation markers. RF production is governed by HLA class II and B cell regulatory loci, associated with mucosal inflammation, and is genetically and molecularly distinct from RA.

Hepatocrinology is an emerging interdisciplinary field that examines the bidirectional interactions between the liver and the endocrine system, emphasizing how hepatic dysfunction influences hormonal regulation and how endocrine disorders, in turn, shape liver metabolism, inflammation, and disease progression. This review summarizes current theoretical frameworks, including hepato-endocrine axes, hepatokine signaling, and multi-organ communication models, highlighting the liver's role as a central endocrine hub. Key hepatic hormones, transport proteins, and hepatokines such as fetuin-A, fibroblast growth factor 21, and selenoprotein P are discussed in relation to metabolic disorders including metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, polycystic ovary syndrome, diabetes, and advanced chronic liver disease. The review further explores hormonal axes involving the thyroid, pancreas, adrenal glands, parathyroids, and gonads, illustrating their complex interplay with hepatic physiology. Current challenges, such as limited long-term studies and therapeutic controversies, are examined alongside emerging directions involving hepatokine-targeted therapies, precision medicine, and microbiome-driven modulation. Understanding these interconnected pathways is essential for improving diagnostic accuracy, risk stratification, and therapeutic strategies in hepato-endocrine disorders.

The overlapping epidemics of chronic viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD) present a complex challenge in modern hepatology. In chronic hepatitis B, a unique "steatosis paradox" emerges: while isolated hepatic steatosis provides a suppressive microenvironment that promotes hepatitis B viral clearance, the concomitant systemic cardiometabolic burden acts dose-dependently to drive fibrogenesis and hepatocellular carcinoma (HCC). Conversely, chronic hepatitis C and host metabolic dysfunctions exhibit synergistic destruction. Hepatitis C virus actively hijacks lipid metabolism and induces insulin resistance. Even after viral eradication via direct-acting antivirals, residual steatosis and glycemic abnormalities remain formidable drivers of HCC. Consequently, the traditional virocentric paradigm is no longer sufficient. Clinical management should pivot toward precision risk stratification and a multidisciplinary dual-target approach, equally prioritizing sustained viral suppression and aggressive metabolic remission. This review summarizes the divergent virus-MASLD interactions, optimal clinical strategies, current challenges and future opportunities.

Host-pathogen interplay of Orientia tsutsugamushi: pathomolecular epidemiology and phylo-immuno profiling in naturally infected rodents and shrews.

This study aimed to evaluate the protective effects of curcumin (Cur) against broiler liver damage caused by exposure to polybrominated diphenyl ether (BDE-209). Four groups of 96 one-day-old broiler chicks were randomly assigned to the control group, the BDE-209 (0.4 g/kg) group, the BDE-209 (0.4 g/kg) + Cur (0.3 g/kg) group, and the Cur (0.3 g/kg) group. Following a 42-day treatment period, intestinal microbiota, hepatic inflammation response, and endoplasmic reticulum stress were assessed. In the gut, BDE-209 caused severe intestinal damage, including shortened villi, increased crypt depth, disrupted tight junction structures, and ultrastructural abnormalities. Curcumin treatment alleviated these pathological changes, restored tight junction protein expression, and improved intestinal barrier function. Curcumin also reversed BDE-209‑induced gut microbiota dysbiosis by increasing beneficial bacteria such as Lactobacillus and reducing harmful bacteria including Proteobacteria. Moreover, curcumin lowered intestinal levels of key pro‑inflammatory cytokines. In the liver, BDE‑209 induced marked histopathological lesions, hepatocyte ultrastructural damage, elevated serum liver enzymes, and increased oxidative stress. Curcumin ameliorated these hepatic alterations, suppressed the activation of NF‑κB and MAPK signaling pathways, and reduced the expression of endoplasmic reticulum stress‑related proteins and genes. Curcumin alleviated BDE-209-induced liver damage in broilers in association with restoration of gut microbiota and reduction of inflammation and ER stress.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and poses a major global health burden. It remains a leading cause of cancer-related death worldwide, with persistently high incidence and mortality in regions affected by chronic viral hepatitis, cirrhosis, alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease. Although surgical resection, liver transplantation, locoregional therapies, molecular targeted agents, and immune checkpoint inhibitors have improved treatment options, outcomes for advanced HCC remain unsatisfactory. Chimeric antigen receptor (CAR) T-cell therapy is an adoptive cellular immunotherapy in which T lymphocytes are genetically engineered to recognize tumor-associated antigens and eliminate malignant cells. CAR-T-cell therapy has achieved major clinical success in hematologic malignancies, but its application in HCC is still developing because of tumor heterogeneity, antigen escape, limited T-cell trafficking, and an immunosuppressive tumor microenvironment. Recent studies have investigated several HCC-associated targets, including glypican-3 (GPC3), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), CD133, epidermal growth factor receptor variant III (EGFRvIII), B7 homolog 3 (B7H3), mucin 1 (MUC1), natural killer group 2 member D ligand (NKG2DL), programmed death-ligand 1 (PD-L1)/c-Met, CD147, CD44, and epithelial cell adhesion molecule (EpCAM). This article provides a target-oriented synthesis of HCC-related CAR-T-cell therapy, summarizes registered clinical studies according to antigen target, CAR design, trial phase, administration route, and available outcomes, and discusses how CAR structural evolution may influence therapeutic development in HCC. This article aims to review recent advances in CAR-T-cell therapy for hepatocellular carcinoma.

Oleanolic acid alleviates hepatic fibrosis by inhibiting liver macrophage recruitment and polarization.

The metabolic dysfunction-associated fibrosis 5 (MAF-5) tool has been proposed for identifying individuals at high risk of liver fibrosis, but its ability to predict liver-related events (LREs) remains unknown. We aimed to evaluate the ability of MAF-5 to predict LREs and assess whether modifications could enhance its predictive capacity. A retrospective cohort of 62,625 adults without cancer, organ transplantation, chronic viral hepatitis, or heavy alcohol intake was followed for LREs (hepatocellular carcinoma and/or liver cirrhosis complications). The MAF-5 score was calculated and compared with other non-invasive liver fibrosis biomarkers. We also assessed whether modifying the MAF-5 score could improve LRE prediction. During a median follow-up of 11.2 years, 147 patients developed LREs. The MAF-5 scores were used to stratify participants by LRE risk into low-, intermediate-, and high-risk categories, with incidence rates of 0.108, 0.576, and 1.520 cases per 1,000 person-years, respectively. Age was identified as an independent risk factor for LREs, and therefore, we developed an age-modified MAF-5 (aMAF-5) score, which showed improved performance (C-index: 0.870 vs 0.818; integrated area under the curve: 0.858 vs 0.784). Within the same MAF-5 category, LRE risk varied according to the aMAF-5 score. The use of "either positive" criteria improved sensitivity (from 0.412 to 0.765) and decreased specificity (from 0.944 to 0.830), while "both positive" criteria improved specificity and reduced sensitivity. Both scores performed well regardless of age, sex, or metabolic syndrome status. The MAF-5 score allows effective stratification of LRE risk. The aMAF-5 score further improves risk stratification. These scores identify individuals at risk of LREs who may benefit from enhanced surveillance.

Metabolic dysfunction-associated steatohepatitis (MASH) represents a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), largely due to metabolic dysregulation and sustained liver inflammation. TNF-α plays a pivotal role in MASH pathogenesis by inducing cell death, inflammation, and decreased insulin sensitivity. In this study we investigated the effects of TNF-α in human precision-cut liver slices (PCLS) under healthy or steatotic conditions, to provide insights into MASH pathogenesis. PCLS were prepared from human liver tissue and cultured in control (WEGG) and hyper-nutritive (GFIPO) mediums with or without TNF-α (50 ng/mL) for 96h. Viability was assessed via ATP content, lipid accumulation by triglyceride (TG) assay, and transcriptomic changes through Next-Generation Sequencing. The protein levels of cytokines, chemokines, and fibrotic mediators released from PCLS were quantified using Luminex assay and ELISA. TNF-α significantly altered the transcriptional profiles in PCLS, inducing pro-inflammatory and pro-fibrotic signaling, and downregulating lipid metabolic processes in both WEGG and GFIPO media. TNF-α showed a trend in elevating intracellular TG in both conditions, albeit not statistically significant. On protein levels, TNF-α supplementation to WEGG medium induced the expression of IL8, CCL2, CCL19, PDGF-AB/BB, TGF-α, and MMP9. GFIPO medium alone induced inflammatory and fibrotic responses indicated by elevated levels of IL8, CCL2, and Pro-collagen 1A1. GFIPO medium with TNF-α supplementation further exacerbated the inflammatory and fibrotic responses, characterized by increased release of cytokines and growth factors. This human PCLS model effectively demonstrated the co-occurrence of key features of MASH, such as steatosis, inflammation, and fibrosis, highlighting the impact of metabolic stress and inflammatory cytokine TNF-α on these disease characteristics, and the potential of the PCLS model in exploring mechanism of MASH progression.

Systemic metabolic dysfunction promotes degenerative diseases in many organs, including liver and kidney. The liver is a master regulator of systemic metal ion homeostasis. Hepatic copper deficiency is increasingly observed in metabolic dysfunction associated steatotic liver disease (MASLD) and is associated with greater disease severity and poor outcomes. However, mechanisms linking copper dysregulation to MASLD and its co-morbidities remain poorly defined. We investigated whether impaired mitochondrial copper homeostasis contributes to MASLD-related pathobiology and represents a modifiable therapeutic axis. Using dietary mouse models of MASLD and in vitro systems, we found that dietary copper deficiency induces lipotoxicity and suppresses mitochondrial metabolic programs. MASLD livers exhibited marked depletion of copper, impaired cytochrome c oxidase integrity, and bioenergetic failure. Targeted restoration of mitochondrial copper with the copper ionophore elesclomol normalized copper-handling programs, improved mitochondrial function, and suppressed ferroptotic stress, hepatocyte senescence, and fibroinflammatory remodeling. Mechanistically, reduced expression of the mitochondrial copper transporter SLC25A3 and MT-CO1 disrupted the SLC25A3-SCO1-MT-CO1-CTR1 axis, limited copper uptake and destabilized copper-iron balance, promoting maladaptive cell fate changes. Across multiple human cohorts and mouse models, copper-iron imbalance tracks with MASLD progression, clinical outcomes, and multiple extrahepatic comorbidities; restoring copper homeostasis in mice with MASLD attenuates both liver and kidney inflammation and fibrosis. Mitochondrial copper deficiency is a mechanistically actionable driver of MASLD that promotes bioenergetic failure, ferroptosis, senescence and fibroinflammatory damage in the liver and other organs. Targeting copper-centered mitochondrial regulation represents a novel biomarker and therapeutic strategy for MASLD and its systemic complications.

RNA-binding protein ZMAT3 protects against MASLD by regulating SEPT11 mRNA stability.

Chronic hepatitis delta (CHD) causes severe chronic viral hepatitis. This study examines the predictors and outcomes of CHD course in a large contemporary cohort. CHD patients with ≥3 years follow-up from the multicentre retrospective D-SOLVE and hepatitis D virus (HDV)-1000 database (6 European centres) were enrolled. Longitudinal changes in biochemical and laboratory markers were analysed. Time-to-event analysis was performed and predictors of liver-related events (LREs) were assessed with univariable and multivariable Cox regression analysis. Among a total of 1004 patients, 565 (56%) with ≥3 years follow-up were included. Patients had a mean (SD) age of 45 (12) years, with 55% men and 60% of European origin. At baseline, 77.8% were HDV RNA+, 39.8% had cirrhosis and 45% had previous interferon therapy. During a median (IQR) follow-up of 55 (46-62) months, 48 patients progressed to cirrhosis at 1, 3 and 5-year cumulative incidence of 1.8%, 5.6% and 13.6%, respectively. De-novo LREs occurred in 47 (9%) patients at 1, 3 and 5-year cumulative incidence of 0.8%, 2.4% and 10.8%, respectively. Cox regression analysis showed that anti-hepatitis C virus+ (adjusted hazard ratio (aHR)=1.72, 95% CI 1.22 to 5.88) and elevated gamma-glutamyl transferase (GGT) (aHR=2.77, 95% CI 1.22 to 6.27) at baseline were significantly associated with cirrhosis onset, while older age (aHR=1.03, 95% CI 1.00 to 1.07), elevated GGT (aHR=4.38, 95% CI 1.81 to 10.57), detectable HDV RNA (aHR=10.32, 95% CI 1.34 to 79.53) and cirrhosis diagnosis (aHR=2.23, 95% CI 1.03 to 4.84) correlated with LREs. The risk for LREs increased from HDV RNA ≥1000 IU/mL, while hepatitis B surface antigen (HBsAg) levels did not correlate with disease progression. In a large real-life cohort of CHD patients, older age, GGT elevation, cirrhosis and detectable HDV RNA were the main determinants of liver-related outcomes, with worse prognosis noted from HDV RNA ≥1000 IU/mL.

Patients living with human immunodeficiency virus 1 (PLWH) develop accelerated liver fibrosis, but the exact mechanism remains unknown. Activation of hepatic stellate cells (HSCs)-a central driver of hepatic fibrogenesis-is influenced by various factors, including viral infection, hepatocellular injury, chronic immune activation, gut barrier dysfunction, and microbial translocation. The role of gram-positive microbial products in human immunodeficiency virus 1 (HIV-1) infection-associated liver inflammation and fibrosis remains poorly understood. This study investigates the effect of lipoteichoic acid (LTA), a major gram-positive bacterial component, on HSCs in the context of HIV-1 infection. Human primary HSCs (pHSCs) were isolated from liver tissues of HIV-1-infected and uninfected individuals undergoing hepatic resection. Inflammatory responses of HSCs to LTA stimulation were measured via ELISA in patient-derived HSCs, and in vitro Lx2 cells (a human HSC line) before and after HIV-1BaL exposure. Western blotting, ChIP-qPCR and RNA-seq were used on Lx2 cells to explore relevant gene associations. LTA modestly induced interleukin-8/CXCL8 (IL-8) production in HSCs, but this response was heightened in both patient-derived HIV-1 exposed pHSCs and in vitro HIV-1BaL exposed Lx2 cells. IL-8 mRNA levels were higher in HIV-1-infected tissues compared to uninfected controls. LTA exposure increased IL-8 mRNA in LX2 cells, and IL-8 treatment of Lx2 cells increased α-SMA and COL1A1 expression. Transcriptomic analysis on Lx2 cells co-exposed to LTA and HIV-1BaL suggested a link between histone acetylation and IL-8. HIV-1 exposure in patient-derived pHSCs and Lx2 cells was linked to increased IL-8 response of HSCs to LTA. In vitro IL-8 treatment of Lx2 cells supports a role of IL-8 in pro-fibrogenic signaling in HSCs. These findings link gut-derived gram-positive microbial products and IL-8 activation in HSCs, providing important insights to guide future mechanistic studies and potential therapeutic targets for managing HIV-associated liver disease.