Hepatic fibrosis (HF) is a progressive condition driven by persistent activation of hepatic stellate cells (HSCs), metabolic dysregulation, and inflammatory signaling. Emerging evidence identifies the nuclear receptor NR1D1 as a central node linking circadian rhythms, HIF-1α signaling, and ammonia-mediated HSC activation, providing a mechanistic framework for chrono-metabolic therapeutic strategies. Preclinical studies demonstrate that pharmacological or natural compound-mediated modulation of NR1D1, including Hedyotis diffusa , ferulic acid, and dihydroartemisinin, restores circadian and metabolic homeostasis, attenuates HSC activation, and reduces extracellular matrix deposition. Integrative chrono-informed interventions leveraging NR1D1 offer potential advantages over conventional single-target therapies by synchronizing drug action with endogenous circadian oscillations, optimizing dosing, and enabling multi-pathway modulation. This review highlights the NR1D1-centered chrono-metabolic axis as a promising therapeutic target for HF, emphasizing translational potential and the need for preclinical and early-phase clinical validation.
BACKGROUND Liver fibrosis (LF), a core pathological process driving chronic liver disease, has no ideal clinical intervention approaches. A fixed Jianpi Huoxue Formula (FJHF), a traditional Chinese medicine (TCM) prescription derived from the Sijunzi Decoction and Taohong Siwu Decoction, has shown clinical benefits against LF. AIM To investigate the mechanism by which FJHF attenuates LF via STAT3/MYC/MCL-1 pathway regulation. METHODS Three strategies were integrated: (1) Clinical single-cell RNA sequencing (scRNA-seq) was performed on liver tissues from three untreated cirrhosis patients and three FJHF-treated patients to characterize hepatic cell heterogeneity and FJHF-responsive gene expression; (2) A randomized controlled trial was conducted in 40 cirrhosis patients with hypersplenism (20 each in the Jianpi Huoxue Formula and control groups) to assess a hepatocellular injury indicator alanine aminotransferase (ALT), hepatic reserve function indicators [total bilirubin (TBIL) and prothrombin time], and fibrosis indicators [hyaluronic acid (HA), laminin, type III procollagen N-terminal peptide (PIIINP), and type IV collagen (CIV)]; and (3) In vitro experiments were performed in human hepatic stellate cells (HSCs) LX-2 using cell counting kit-8, transmission electron microscopy, western blotting, and quantitative real-time PCR to verify the regulatory role of FJHF in the STAT3/MYC/MCL-1 pathway. RESULTS FJHF modulated the proportion of HSC populations in a small-sample scRNA-seq cohort. According to clinical data, FJHF treatment significantly decreased ALT (P < 0.01), TBIL (P < 0.05), and the fibrosis markers HA, PIIINP, and CIV (P < 0.05) compared to the control group. In vitro , 20% FJHF-containing serum suppressed HSC activation, as indicated by reduced α-SMA, collagen I, and TIMP1 levels and elevated MMP1 levels. Notably, FJHF inhibits the STAT3/MYC/MCL-1 pathway to ameliorate LF. CONCLUSION Short-term FJHF intervention improves early biochemical abnormalities in LF by inhibiting the STAT3/MYC/MCL-1 pathway and suppressing HSC activation. This work provides a scientific basis for the application of FJHF and identifies the STAT3/MYC/MCL-1 axis as a potential target for TCM intervention in early LF metabolic abnormalities.
Liver failure, which includes acute liver failure (ALF) and acute-on-chronic liver failure (ACLF), is a life-threatening condition characterised by severe loss of hepatocytes, systemic inflammation, and multi-organ dysfunction, often leading to mortality rates exceeding 50%. Therapeutic plasma exchange (TPE, also known as plasmapheresis) and continuous renal replacement therapy (CRRT) are essential extracorporeal treatments that detoxify the blood, stabilise patients, and act as a bridge to recovery or transplantation. The debate surrounding the use of TPE and CRRT in liver failure (ALF and ACLF) is ongoing, with a recognised need to clearly define the patient groups, timing, and modality of application. This minireview synthesises evidence from 2016 to 2025, obtained from PubMed, EMBASE, and the Cochrane databases, and examines the mechanisms, indications, protocols, and outcomes of TPE and CRRT in ALF and ACLF. Correct patient selection, timing, and monitoring are essential to optimise benefits while minimising risks such as bleeding, infections, or citrate toxicity. This review examines various aspects of both therapies to help determine the most suitable treatment for liver failure. It highlights the importance of standardised guidelines to improve outcomes across different settings.
Hepatocellular carcinoma (HCC) is frequently diagnosed without tissue confirmation, and single-site biopsies often fail to capture intratumor heterogeneity, underscoring the need for liquid biopsy approaches. Circulating cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) provide access to genetic, epigenetic, copy-number, and fragmentomic biomarkers that can support diagnosis, prognostication, and treatment monitoring. Current monitoring modalities, such as alpha-fetoprotein and radiographic assessment, lack sensitivity and typically lag behind molecular changes, whereas cfDNA/ctDNA-based analyses offer the potential for earlier and more accurate prediction of treatment response and disease dynamics. Literature review (PubMed, Google Scholar, 2015-2025) evaluated cfDNA biomarkers for predicting and monitoring treatment response across immune checkpoint inhibitors, tyrosine kinase inhibitors, transarterial chemoembolization, and radiotherapy in HCC. ctDNA profiling detects recurrent mutations in TERT , TP53 , CTNNB1 , and phosphatidylinositol 3-kinase/mammalian target of rapamycin pathways with variable prognostic associations across therapies. Limited evidence suggests phosphatidylinositol 3-kinase/mammalian target of rapamycin alterations may predict tyrosine kinase inhibitor resistance. Serial ctDNA monitoring shows promise for early response assessment, with variant allele frequency changes correlating with outcomes in small cohorts, though superiority to alpha-fetoprotein remains inconsistently demonstrated. Baseline cfDNA burden associates with survival across multiple treatment modalities. Copy-number variation dynamics correlate with transarterial chemoembolization response. Postoperative ctDNA detection enables recurrence risk stratification. Fragmentomic and methylation signatures demonstrate high diagnostic accuracy but lack treatment-response validation. cfDNA shows potential for treatment monitoring in HCC but faces critical limitations: Low analytical sensitivity, platform heterogeneity, absence of validated thresholds, and limited prospective evidence. Standardized multicenter trials demonstrating clinical utility are essential before routine implementation.
Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disease of complex and multifactorial origin, arising from the interplay of genetic susceptibility and environmental triggers. Among infectious factors, hepatitis A virus (HAV) infection has emerged as a potential precipitant of autoimmune responses leading to AIH onset. This mini-review explores the current understanding of HAV-induced AIH, summarizing available literature on its epidemiology, proposed immunopathogenic mechanisms, and diagnostic challenges. Special attention is given to the overlap between acute viral hepatitis and autoimmune activation, as well as the clinical and histological features that may distinguish secondary autoimmune phenomena from de novo AIH. The review is complemented by clinical experience drawn from a recently observed case of HAV-triggered AIH in a young adult, which illustrates the diagnostic complexity and therapeutic responsiveness of such presentations. Management strategies, including corticosteroid-based immunosuppression and long-term monitoring, are also discussed in the context of recent evidence and international guidelines. Recognizing HAV as a potential trigger of AIH is essential for timely diagnosis, optimal treatment selection, and prevention of disease progression in affected patients.
Acute mesenteric ischemia is a rare but often fatal complication in patients with cirrhosis. A combination of circulatory changes, endothelial dysfunction, and unstable coagulation increases the risk of both occlusive and non-occlusive forms. Yet, due to nonspecific symptoms and clinical overlap with other complications of cirrhosis, diagnosis is frequently delayed. In this review, we describe the pathophysiologic mechanisms that underlie acute mesenteric ischemia in cirrhosis and outline current diagnostic and management strategies. Computed tomography angiography remains the first-line imaging modality, while laboratory findings are supportive but not diagnostic. Medical treatment includes fluid resuscitation, early anticoagulation, and infection control, with vasodilator therapy considered in select cases. Surgical intervention may be required in the setting of bowel infarction or confirmed vascular occlusion, but the risks in patients with cirrhosis are significant and require careful assessment. We also review four published case reports, which illustrate a range of clinical presentations, diagnostic challenges, and outcomes. Together, these cases highlight the need for early imaging, attention to thrombotic risk, and thoughtful use of both medical and surgical therapies. Ongoing research is needed to guide management in this high-risk population.
We read with great interest the article by Dai et al recently published in World Journal of Hepatology . The authors developed a novel nomogram incorporating L59, platelet count (PLT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) that demonstrates impressive discriminative performance (area under the curve 0.921-0.959) for predicting evident histological liver injury in patients with chronic hepatitis B (CHB). This model represents a meaningful advance in non-invasive risk stratification and holds promise for optimizing clinical decision-making and resource allocation. Particularly noteworthy is the inclusion of L59, a degradation product of the latency-associated peptide (LAP) of transforming growth factor-β (TGF-β). As highlighted in foundational studies, L59 reflects in vivo TGF-β activation-a central driver of hepatic stellate cell activation and collagen deposition. Its elevation in blood correlates with early fibrogenic activity, providing insight into ongoing fibrosis that may not be captured by static markers. Concurrently, ALT and AST serve as well-established surrogates for hepatocellular inflammation and necroinjury, while thrombocytopenia (low PLT) mirrors portal hypertension and advancing architectural distortion. Together, these markers account for the two fundamental disease-driving processes of CHB progression: Inflammation-driven injury and fibrosis-mediated scarring. This commentary discusses the conceptual advance represented by the L59-based model while highlighting practical limitations related to assay availability, cost, and standardization that currently restrict its routine clinical implementation. Using the Dai et al model as a framework, we further argue that non-invasive evaluation in CHB should increasingly adopt a dual approach that assesses both fibrosis and steatosis, particularly in patients with concurrent metabolic dysfunction-associated steatotic liver disease. In this growing population, reliance on fibrosis assessment alone may underestimate disease severity and delay appropriate risk stratification. Overall, this commentary highlights the need for an integrated non-invasive evaluation of both steatosis and fibrosis, particularly in patients with mixed viral and metabolic liver disease etiologies.
Artificial intelligence (AI) has emerged as a powerful tool in the field of hepatology, offering new opportunities to enhance diagnosis, risk stratification, and therapeutic decision-making. AI models have demonstrated improved performance compared with conventional methods by integrating complex multimodal datasets. These models have shown promising results across a broad spectrum of liver disease management. Despite these advances, unmet needs remain a significant barrier to the full integration of AI models into clinical practice. Future progress will depend on developing interpretable, well-validated AI systems supported by multicentre collaborations and robust data infrastructure. In this comprehensive review, we summarise the current applications of AI in hepatology, highlight areas of significant clinical promise, and outline the challenges and future directions necessary for safe, equitable, and effective integration into routine practice.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prominent metabolic disease characterized by hepatic steatosis, inflammation, and progressive liver damage, in which oxidative stress plays a crucial pathogenic role. Increasing attention has been drawn to the contributions of a high fat diet (HFD) and gut dysbiosis in the onset and progression of MASLD. These factors compromise intestinal barrier integrity, promote endotoxemia, induce lipid peroxidation, and activate pro-inflammatory signaling pathways, contributing to oxidative stress. Excessive production of reactive oxygen species disrupts hepatic redox homeostasis, impairs mitochondrial function, and amplifies inflammatory responses, thereby accelerating hepatic fibrosis and disease progression. This review highlights the triangular and synergistic relationship among HFD, gut dysbiosis, and oxidative stress in MASLD pathogenesis. It provides a comprehensive overview of antioxidant interventions, including lifestyle modifications, dietary antioxidants, natural bioactive compounds, and pharmacological agents, aiming at providing promising MASLD management in future clinical applications.
The core lethal complications of liver cirrhosis, particularly portal hypertension and hepatic decompensation, are closely linked to dysregulated pathological angiogenesis. Aberrant neovascularization is primarily driven by the hypoxia-inducible factor-vascular endothelial growth factor (VEGF) axis. Activated hepatic stellate cells release key factors like VEGF and platelet-derived growth factor, promoting endothelial cell proliferation. Inflammatory-oxidative stress signals (e.g. , tumor necrosis factor-alpha/interleukin-6 and non-alcoholic fatty liver disease oxidase-derived reactive oxygen species) amplify this process via the nuclear factor kappa-B pathway. Activation of the local renin-angiotensin system also exacerbates vascular leakage and malformation through pathways like angiotensin II. Preclinical studies demonstrate that drugs targeting these pathways (e.g. , the anti-VEGF agent bevacizumab, the multi-kinase inhibitor sorafenib) can effectively inhibit pathological angiogenesis. However, their clinical translation faces three major challenges: (1) Intrahepatic vascular heterogeneity limits targeting efficiency; (2) Activation of compensatory pathways (e.g. , FGF/Notch) leads to treatment resistance; and (3) Systemic administration carries off-target risks. Future breakthroughs hinge on developing biomarkers based on single-cell sequencing, applying novel models like the “hepatic hypertension-chip”, and implementing multi-target combination therapies.
Hyperimmunization-defined by the presence of pre-formed donor-specific antibodies or a positive donor–recipient crossmatch-remains a pivotal immunological challenge in liver transplantation (LT), linked to substantially elevated risks of acute rejection and graft dysfunction. In their recent work, EL-Domiaty et al published in the World Journal of Hepatology evaluate a targeted induction strategy combining rabbit anti-T-lymphocyte globulin and high-dose intravenous immunoglobulin in hyperimmunized liver transplant recipients. Using a rigorous matched case-control design, the team demonstrates that this induction approach yields rejection rates, graft survival, and patient outcomes on par with those seen in non-immunized recipients, with no excess of severe infectious complications. This editorial situates these valuable findings within the evolving body of literature on antibody-mediated injury in LT, offers a critical appraisal of the study’s methodology and real-world clinical implications, and explores how such induction strategies can shape the future of personalized immunosuppressive care for immunologically high-risk liver transplant patients.
Gallbladder cancer (GBC) remains one of the most lethal gastrointestinal malignancies, characterized by aggressive biology and poor survival. Despite advances in molecular profiling and systemic therapies, innovations have not translated into proportional survival gains in many regions, suggesting underrecognized determinants of prognosis. In this opinion review, we argue that healthcare system logistics represent a critical, modifiable factor influencing GBC outcomes. In intermediate-incidence settings, such as Latin America, many cases are diagnosed incidentally following cholecystectomy. In this context, timely referral for radical re-resection represents a critical component of curative-intent management; however, delays in diagnosis and staging frequently compromise this therapeutic window. Emerging evidence indicates that system-level inefficiencies may impact survival more than traditional clinical variables. We explore the interplay between tumor biology and healthcare delivery, highlighting molecular stratification, surgical centralization, and multidisciplinary coordination. Additionally, we address controversies in incidental GBC, including optimal timing of re-resection and perioperative systemic therapy. We propose that healthcare logistics be formally recognized as a prognostic factor. Bridging the survival gap requires both oncologic advances and structural optimization of care pathways to ensure timely access to curative treatment.
