anscriptome and proteome sequencing analyses of lenvatinib-resistant cell lines and patient tissues to identify critical genes and proteins associated with lenvatinib resistance. Subcutaneous mouse models were established, the half maximal inhibitory concentration (IC50) was determined, and colony formation assays were employed to investigate the biological role of microtubule-associated serine/threonine kinase-like (MASTL) in tumor progression and therapeutic resistance. Molecular and biochemical methodologies, including RNA sequencing, chromatin immunoprecipitation sequencing, and mass spectrometry, were employed to explore the underlying mechanisms by which MASTL contributes to poor responses to lenvatinib in HCC. Results: MASTL was frequently upregulated in lenvatinib-resistant HCC cells and tissues. Increased expression of MASTL drove lenvatinib resistance through reactivation of mitogen-activated protein kinase (MAPK) signaling pathways, which is typically inhibited by lenvatinib

illance. While thermal ablation has been established to cause immediate cell death in the center of the thermal ablation zone, its metabolic impact in the peri-ablational region remains unclear. We aimed to elucidate the metabolic mechanism by which Galectin-1 (Gal-1) promotes thermal-ablation-induced hyperthermia resistance in HCC and demonstrate the therapeutic potential of inhibiting Gal-1 in combination with thermal ablation in vivo. Approach and Results: Proteomic analysis was performed using an untargeted approach on pre-ablation formalin-fixed paraffin-embedded (FFPE) biopsy specimens of thermal ablation responders (n=32) and nonresponders (n=23). Gal-1 was found to be overexpressed in thermal ablation nonresponders compared to responders. Moreover, HCC with Gal-1 overexpression demonstrated reduced sensitivity to hyperthermia in vitro and increased utilization of glycolysis and downstream TCA cycle under hyperthermia-induced stress. Gal-1-overexpressing HCC enhanced its metabol

llenges this notion, revealing immune activation, HBV DNA integration, and potential oncogenic processes even in the absence of elevated ALT. The IT phase’s prolonged high viral replication raises concerns about its implications for hepatocellular carcinoma (HCC) risk. Histological studies show that significant inflammation and fibrosis may exist in patients meeting IT criteria, suggesting that the current definitions may underestimate disease activity. Treatment during the IT phase remains controversial, with international guidelines largely recommending against antiviral therapy due to its limited efficacy and potential risks. However, subsets of IT patients may benefit from early intervention. The risks and benefits of therapy in IT CHB are not fully understood, and the lack of consensus regarding treatment thresholds further complicates clinical decision-making. This review highlights the importance of redefining IT CHB to include virological and histological parameters and calls f

has not been documented. We identified TAF2 mRNA and protein overexpression in human HCC cells and tissue samples, compared to their normal counterparts. A significant negative correlation between TAF2 levels and overall survival of HCC patients was observed. The role of TAF2 in HCC regulation was examined using a hepatocyte-specific conditional knockout mouse (Taf2ΔHEP), TAF2 knockdown and overexpressing human HCC cells, and TAF2 overexpression in mouse liver by hydrodynamic approach. As a core component of basal transcription machinery, TAF2 is required for hepatocyte survival. As such, in Taf2ΔHEP mice there were hepatocyte death and compensatory proliferation, contributing to an inflammatory/fibrotic milieu favoring HCC. Accordingly, N-nitrosodiethylamine (DEN)/high fat high sugar diet-induced HCC was robustly augmented in Taf2ΔHEP mice compared to their wild-type littermates. TAF2 overexpression in mouse liver did not lead to tumor development, but significantly augmented HCC that

is critical to guide prognosis and management due to their increased risk of liver decompensation and hepatocellular carcinoma. In addition, identification of At-Risk MASH will assist in targeting those eligible for pharmacotherapy. Screening pathways for detecting advanced liver fibrosis consisting of sequential FIB-4 and elastography or direct liver fibrosis biomarkers in patients with clinical risk factors are recommended, however have sub-optimal sensitivity and specificity. Biomarkers based on serum and/or elastography for At-Risk MASH have been developed in specialist centres however lack broad validation, particularly in the community. Currently a range of barriers have retarded adoption of liver fibrosis screening in primary care, including knowledge gaps regarding non-invasive testing, cost and limited access of non-invasive tests and lack of integrated ordering and reporting systems. Once target patients are identified, robust pathways for linkage to specialist care are neede

d adverse events (imAEs) and improved OS. We assessed potential associations between the occurrence of imAEs and OS, and temporal patterns of imAEs, in HIMALAYA. Approach and Results: OS in participants who did and did not experience imAEs and the frequency and timing of imAEs were assessed for STRIDE and durvalumab in the safety analysis set of HIMALAYA. imAEs occurred in 139/388 (35.8%) and 64/388 (16.5%) participants with STRIDE and durvalumab, respectively; most were low grade. OS HRs (95% CI) in participants who experienced imAEs versus those who did not were 0.73 (0.56–0.95) for STRIDE and 1.14 (0.82–1.57) for durvalumab. The 36-month OS rate (95% CI) for STRIDE was 36.2% (28.1–46.7) and 27.7% (22.4–34.2) in participants who did and did not experience imAEs, respectively. The most common imAE category with STRIDE was endocrine events (16.5%). Most imAEs occurred ≤3 months after treatment initiation. Conclusions: Participants who experienced imAEs with STRIDE had a numerical impro

in fatty acid synthesis and inflammatory pathways, suggesting a regulatory role for ECM1 in liver steatosis. Here, we studied the role of ECM1 in metabolic dysfunction–associated steatotic liver disease pathogenesis and underlying mechanisms. Approach and Results: Hepatic ECM1 expression was evaluated and found to be significantly reduced in liver samples from patients with metabolic dysfunction–associated steatohepatitis (MASH), and in 4 established MASH mouse models (HFD, MCD, HFHC, and ob/ob−/−). Although overexpression of ECM1 effectively blocked hepatic insulin resistance, steatosis, and inflammation, ECM1 ablation exacerbated diet-induced MASH progression. Mechanistically, ECM1 interacted with the K-homology 3 (KH3) domain of poly r(C) binding protein 1 (PCBP1) to suppress iron overload, mitigating lipid peroxidation and consequently impeding MASH advancement under metabolic stress. Re-expression of ECM1 and PCBP1 ameliorated liver disease progression. Conclusions: Our study reve

rable increases in ductal plate cell/cholangiocyte differentiation and impaired periportal hepatocyte maturation. We found that the transient enrichment of periportal region-localized T-bet+ Treg cells and their expression of proenkephalin (PENK) are crucial for coordinating hepatocyte and cholangiocyte differentiation in this region. T-bet deletion in Treg cells impacts their acquirement of a tissue residence signature and their PENK expression. Depletion of Penk in Tregs or the administration of naltrexone, an antagonist of the opioid growth factor receptor (OGFr), results in similar liver defects. The supplementation of PENK-derived methionine enkephalin (Met-ENK) reduces ductal plate cholangiocytes and enhances hepatocyte maturation in mice lacking T-bet+ Tregs and in 3-dimensional hepatocyte culture. Molecularly, the Met-ENK/OGFr axis counteracts periportal Notch signaling by downregulating Adam10 expression and promotes adult splicing program by upregulating Esrp2 expression. Our