Antiviral treatment for chronic HBV infection in the "high-replicative low-inflammatory" phase has not been widely recommended. This study aimed to evaluate the safety and efficacy of antiviral therapy in this patient population and analyze peripheral immunological characteristics in relation to treatment response. In this randomized controlled trial, HBeAg-positive patients with normal ALT and elevated HBV DNA were randomly allocated 1:1 to receive TAF 25 mg/day or observation. The primary endpoint was the decline from baseline in HBsAg at Week 48. Secondary endpoints included HBV DNA response rates and the magnitude of HBV DNA reduction. The treatment group was further divided into virological response (VR) and low-level viremia (LLV) subgroups based on HBV DNA response at Week 48. PBMCs from VR (n = 3) and LLV (n = 3) patients underwent scRNA-seq for comparative immunological analysis. A total of 59 patients were allocated to the treatment (n = 30) and control (n = 29) groups. No serious adverse events occurred, except for one control patient who developed an ALT flare and required antiviral initiation. At Week 48, the treatment group demonstrated significantly greater reductions in HBsAg (0.19 vs. 0 log10 IU/mL, p = 0.005) and HBV DNA (6.32 vs. 0.19 log10 IU/mL, p < 0.001) compared to controls. In the treatment group, 20% achieved HBV DNA < 20 IU/mL and 3.3% achieved HBeAg seroconversion, while none occurred in the untreated patients. PBMCs scRNA-seq revealed dominant distributions of NK_FCER1G, NK_KLRF1, NK_XCL1, and NKT_FCGR3A subclusters in the VR group, with upregulated expression of genes such as SLC27A4 and PTMA. Taken together, our findings revealed that TAF demonstrates favorable safety and antiviral efficacy in patients with high-replicative, low-inflammatory HBV infection during the 48-week follow-up period, although complete virological suppression rates remain suboptimal. NK-mediated mechanisms may contribute to antiviral success. Trial Registration: The trial was registered on ClinicalTrials.gov (NCT04231565).

Non-alcoholic fatty liver disease (NAFLD) affects approximately 25% of the global adult population and represents a major public health burden, characterized by disease progression from steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and potentially hepatocellular carcinoma. Despite this high prevalence and serious clinical outcomes, no pharmacologic therapies are currently approved, and standard lifestyle interventions often prove ineffective. Therefore, there is a major unmet clinical need for innovative treatments. To overcome these limitations, nanomedicine has emerged as a promising approach, with multifunctional nanoplatforms (MFNs) demonstrating distinctive advantages in tackling the complex pathology of NAFLD. For instance, MFNs enable targeted liver delivery, synergistic therapeutic effects (eg, reducing hepatic lipogenesis and fibrosis), and theranostic integration, thereby minimizing rapid clearance and adverse effects associated with conventional low-molecular-weight compounds. Consequently, this review comprehensively synthesizes the latest advances in MFNs for NAFLD management, critically analyzing their design strategies (eg, nanoencapsulation of bioactive compounds for enhanced bioavailability) and mechanistic roles in ameliorating inflammation, fibrosis, and steatosis. Furthermore, it explores challenges such as optimizing organ-specific targeting and personalized applications, while outlining future research directions to accelerate clinical translation and address coexisting conditions like chronic hepatitis B infection. By bridging current knowledge gaps, this work aims to inform the development of effective nanotherapeutic strategies for NAFLD.

Chronic hepatitis B virus (HBV) infection remains a major cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide, with more than 250 million people living with chronic infection despite effective prophylactic vaccination. While current treatments provide durable suppression of viral replication and reduce liver-related complications, they rarely achieve functional cure, defined as sustained hepatitis B surface antigen (HBsAg) loss after treatment cessation. Viral persistence is maintained by intrahepatic covalently closed circular DNA and HBV DNA integration, which sustain antigen production and contribute to immune dysfunction. This review summarizes current understanding of HBV immunopathogenesis across acute resolution and chronicity, emphasizing the compartmentalized and tolerogenic liver microenvironment, impaired innate sensing, and progressive dysfunction of HBV-specific B- and T-cell responses, including exhaustion phenotypes shaped by antigen specificity and intrahepatic priming. We also discuss immune correlates associated with functional cure, including partial restoration of polyfunctional HBV-specific T cells and intrahepatic immune remodeling. Finally, we discuss human clinical trials of immune-based therapies highlighting emerging combination strategies designed to couple antigen reduction with immune restauration, defined as the recovery of functional HBV-specific antiviral responses. Collectively, preclinical and clinical data suggest that achieving durable off-treatment control will likely require approaches that address both viral replication, antigen burden and HBV-specific immune responses.

Previous studies based on clinical data from hepatitis C virus and hepatitis E virus infections revealed a deterministic evolution of quasispecies structure, irrespective of haplotype identities, towards a flat-like landscape, characterized by the absence of dominance and high evenness, combined with high haplotype synonymy. Here, two idealized limiting quasispecies states, A and Z, are defined, and it is shown that the A-to-Z evolution describes a parabolic trajectory between these states. The initial phase is dominated by increasing genetic diversity, whereas the subsequent phase is driven primarily by increasing evenness in the haplotype distribution. This evolutionary progression confers a broad domain within the genetic space, resulting in increased fitness and resilience, accompanied by a diminished response to antiviral therapies and multiple escape routes. Finally, a normalized quasispecies maturity score is proposed to position a given quasispecies along this structural evolutionary trajectory. This conceptual framework helps to account for the challenges in treating advanced chronic infections in which therapeutic failure frequently occurs in the absence of resistance-associated mutations.

Liver fibrosis is a common pathological process, leading to the development of end-stage liver diseases. It is triggered by various etiological drivers including viral hepatitis, metabolic-associated steatotic liver disease (MASLD), and cholestasis. Given the substantial impact of liver fibrosis on individuals and its associated mortality rates, effective management of this condition is crucial for improving public health. Despite a growing number of preclinical studies and clinical trials, a systematic synthesis remains lacking. In this review, the molecular panorama of liver fibrogenesis is summarized at first, encompassing etiological drivers of chronic liver injury, key cellular players, core signaling pathways, and extracellular matrix dynamics. Therapeutic interventions in preclinical or clinical stages are systematically classified into two main categories: etiological treatment as the foundational approach and mechanism-based antifibrotic therapies. Emerging and future therapeutic strategies, including those targeting gut-liver axis, gut microbiota, and cell-based therapies, are also addressed along with inherent challenges. Furthermore, future perspectives centered on precision medicine, combination therapies, novel target discovery, and advanced drug delivery systems are emphasized. This review offers a comprehensive overview of the etiologies, diagnostic approaches, pathogenic mechanisms, current development of antifibrotic agents, and prospects for future therapeutic directions of liver fibrosis.

BACKGROUND Splenic marginal zone lymphoma (SMZL) is a low-grade B-cell lymphoma associated with chronic hepatitis C infection. It typically presents with diffuse splenomegaly rather than a focal splenic mass. Focal splenic lesions with vascular enhancement patterns are usually due to vascular tumors which may be benign or malignant, examples of which include sclerosing angiomatoid nodular transformation, hemangiomas, or angiosarcomas. CASE REPORT A 60-year-old man with newly diagnosed hepatitis C-related Child-Pugh A cirrhosis was incidentally found to have a splenic lesion during index abdominal imaging. He was initiated on hepatitis C treatment and successfully achieved a sustained virologic response. Despite viral eradication, serial imaging over 3 years demonstrated a sudden increase in size from 3.3 cm to 5.7 cm. Multiphasic computed tomography (CT) of the abdomen demonstrated a progressive peripheral-to-central enhancement pattern, mimicking a vascular splenic tumor. A review by a multidisciplinary tumor board recommended splenectomy due to progressive enlargement, rupture risk, and inability to exclude a malignant lesion. Histopathological examination revealed SMZL with extensive central infarction and granulomatous reaction, confirming the diagnosis with characteristic biphasic architecture and CD20-positive B-cell populations. No features of aggressive transformation were identified. CONCLUSIONS Our case highlights an unusual presentation of SMZL as a focal splenic mass, rather than diffuse splenomegaly, which grew despite hepatitis C eradication. Tumor infarction and slow organization can produce radiologic features that mimic vascular splenic lesions. This demonstrates the importance of clinicoradiological-pathological correlation and the necessity of histological confirmation in indeterminate splenic masses to avoid delays in management.

While liver biopsy is the gold standard for assessing liver fibrosis, the optimal scoring system for Fontan-associated liver disease (FALD) is debated. This study was to determine the correlation and agreement between the METAVIR score, used for chronic hepatitis, and the Congestive Hepatic Fibrosis Score (CHFS), specifically designed for congestive hepatopathy. We conducted a retrospective review of liver biopsies from 38 Fontan patients. Pathologists independently evaluated each biopsy and assigned a METAVIR fibrosis score and a CHFS. Fontan patients, a mean age of 21 ± 6 years, have undergone the Fontan operation at a mean age of 8 ± 4 years. This established a mean postoperative interval of 13 ± 4 years at the time of study enrollment. When comparing the two scoring systems, the overall weight Kappa of 0.92 suggested perfect agreement between the two methods for assessing the degree of liver fibrosis. However, a subgroup analysis of weight kappa agreement revealed significant differences based on fibrosis severity. In the low-grade fibrosis group, the agreement was substantial agreement (kappa 0.70). In sharp contrast, the high-grade liver fibrosis group (METAVIR F3-F4 and CHFS stages 3-4) demonstrated perfect agreement (kappa 0.90) between the two scoring systems. Overall, METAVIR and CHFS demonstrate strong correlation and agreement. Differences observed in early-stage fibrosis likely arise from their distinct architectural emphases; portal-based in METAVIR versus centrilobular in CHFS.