Hepatology最新文献

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality. Optimal treatment decisions are challenging, and existing treatment allocation frameworks may not fully reflect the evolving therapeutic landscape or contemporary clinical practices in North America. Using a modified Delphi process, a multidisciplinary panel of 20 North American experts in hepatology, medical oncology, surgery, radiology, and radiation oncology developed a consensus-based treatment framework for HCC, termed the BEACON-HCC system. The framework was informed by current evidence and expert opinion through iterative discussion and voting. In a pilot study using 29 real-world patient cases, we assessed concordance between external expert recommendations and BEACON-HCC recommendations and Barcelona Clinic Liver Cancer (BCLC) 2025 treatment recommendations. The BEACON-HCC treatment allocation framework diverges from prior frameworks by incorporating nuanced clinical features such as the degree of intrahepatic tumor burden and vascular invasion, and adverse tumor prognostic markers, to align treatment allocation with tumor biology and therapeutic potential. Key innovations include the incorporation of emerging modalities such as external beam radiation therapy (EBRT), transarterial radioembolization (TARE), and systemic-locoregional combination therapies. In the pilot exercise, expert treatment decisions showed 96.6% concordance with BEACON-HCC recommendations and 72.4% concordance with BCLC recommendations. In conclusion, BEACON-HCC is a consensus-based framework for treatment allocation that incorporates the expanding range of therapeutic options available to patients in the North American HCC population. Expert treatment decisions showed a high concordance with the BEACON-HCC system; further validation using empiric clinical data is planned through the HCC-Live Consortium.

Background and aims: Liver fibrosis and cirrhosis are major global health burdens with limited treatments. Activated HSCs drive fibrosis through increased proliferation, migration, collagen deposition and glycolysis. The aim of this study is to elucidate the signaling events that lead to enhanced glycolysis, subsequent HSC activation, and liver fibrosis.

Approach and results: Utilizing a phospho-kinase array, we identified with no lysine kinase 1 (WNK1) as a new kinase in primary human HSCs activated by the profibrotic PDGF-B. PDGF-mediated glycolysis in HSCs was attenuated by the WNK1 selective inhibitor, WNK-IN-11, as measured by live-cell metabolic assay, Glifon-300 fluorescence, Glucose-Glo assay, and glucose transporter 1 immunofluorescence. To understand how WNK1 promotes glycolysis, we employed chemical genetics where an engineered WNK1 carrying threonine 301 to glycine mutation (WNK1 T301G ) mutant with a modified ATP pocket accommodated a specific ATP-γ-S analogue to thio-phosphorylate its substrates. Thio-phosphorylated proteins were analyzed by mass spectrometry, which identified the glycolytic protein, triosephosphate isomerase 1 (TPI1), as a novel WNK1 direct substrate. TPI1 interacted with WNK1 in condensates, membrane-less phase separation structures. Condensate disruption and knockdown of TPI1 or WNK1 reduced HSC proliferation and migration in vitro. In vivo, pharmacological or genetic WNK1 inhibition significantly attenuated liver fibrosis in carbon tetrachloride and high-fat, choline-deficient, L -amino acid diet mouse models. Finally, WNK1 inhibition reduced fibrogenesis ex vivo in human precision-cut liver slices.

Conclusions: These findings identify WNK1 as a previously unrecognized kinase that promotes HSC activation and liver fibrosis via TPI1-mediated glycolysis, highlighting the WNK1-TPI1 axis as a potential therapeutic target.

Background: Finite therapy resulting in sustained hepatitis B surface antigen (HBsAg) loss for patients with chronic HBV infection (CHB) is an important therapeutic goal. In patients with HBeAg-negative infection, nucleos(t)ide analog (NA) withdrawal may achieve HBsAg loss in 5%-20% of patients after 3 years. Pegylated interferon (PEG-IFNα) is a recognized treatment for CHB.

Methods: NUC-B was a randomized, multicenter trial in NA-treated non-cirrhotic HBeAg-negative patients with CHB. Patients were allocated to either NA withdrawal alone (control) or NA withdrawal followed by a 16-week course of PEG-IFNα 180 μg weekly commencing 4 weeks after NA cessation (PEG-IFNα). The primary endpoint was HBsAg loss at 3 years.

Results: The target recruitment of 240 patients was not achieved. In all, 156 patients, 82 to the control arm, 74 to the PEG-IFNα arm, were recruited between 2017 and 2021; median age 45 years, 24% female, HBV genotypes-A 16%, B 6%, C 4%, D 24%, E 22%, other 1%, ānd unknown 26%. At 3 years, 3% of patients in the control arm and 14% of patients in the PEG-IFNα arm lost HBsAg (OR 5.39; 95% CI (1.11, 26.19); p =0.037). In the control arm, 34.9% of patients returned to NA therapy compared with 28.4% in the PEG-IFNα arm. Exaggerated flares occurred in 27.9% of patients in the control arm compared with 13.4% in the PEG-IFNα arm.

Conclusions: The use of adjuvant PEG-IFNα therapy after withdrawal of NA therapy increases the rate of HBsAg loss while simultaneously reducing the number of exaggerated flares.

Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of HCC, particularly in obesity, yet mechanisms linking hepatocyte dysfunction to tumorigenesis remain unclear. Mixed lineage kinase domain-like protein (MLKL), the effector of necroptosis, is elevated in MASLD, but its hepatocyte-intrinsic role in obesity-driven MASLD-HCC is unknown.

Approach and results: Using a long-term western diet (WD)-induced MASLD-HCC model in hepatocyte-specific MLKL knockout ( MlklHepKO ) mice, we defined MLKL's hepatocyte-intrinsic function. WD increased hepatocyte MLKL protein expression without detectable necroptosis activation, indicating a necroptosis-independent role. MLKL deficiency did not alter WD-induced inflammation, fibrosis, or liver injury but increased hepatic lipid accumulation while reducing lipotoxic lipid species and preserving mitochondrial function. WD-fed MlklHepKO mice developed fewer and smaller tumors with reduced incidence, multiplicity, proliferation, and stemness. Transcriptomic analysis revealed upregulation of mitochondrial oxidative phosphorylation pathways in MlklHepKO livers. WD suppressed the mitochondrial fusion protein and tumor suppressor mitofusin 2 (MFN2), whereas MLKL deficiency restored MFN2 expression post-translationally. In HCC cells, MLKL deletion reduced proliferation, improved mitochondrial respiration, and decreased glycolysis; these effects were reversed by MFN2 deletion. MLKL is localized to nuclear and mitochondrial compartments, consistent with organelle-intrinsic functions. The human MLKL inhibitor necrosulfonamide (NSA) suppressed HepG2 xenograft growth, and elevated MLKL expression in human HCC correlated with poorer overall survival.

Conclusions: Hepatocyte MLKL promotes MASLD-associated HCC through a non-necroptotic mechanism involving MFN2 suppression, impaired mitochondrial function, and increased tumor proliferation and stemness. These findings identify MLKL as a potential therapeutic target in MASLD-associated HCC.