Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Surgical management, including hepatic resection, liver transplantation, and ablation, offers the greatest potential for a curative approach. This review aims to discuss recent advancements in HCC surgery and identify unresolved issues in the field. Treatment selection relies on the BCLC staging system, with surgical therapies primarily recommended for early-stage disease. Recent studies have shown that patients previously considered unresectable, such as those with portal vein tumor thrombus and uncomplicated portal hypertension, may benefit from hepatic resection. Minimally invasive surgery and improved visualization techniques are also explored, alongside new techniques for optimizing future liver remnant, ex vivo resection, and advancements in hemorrhage control. Liver transplantation criteria, particularly the long-standing Milan criteria, are critically examined. Alternative criteria proposed and tested in specific regions are presented. In the context of organ shortage, bridging therapy plays a critical role in preventing tumor progression and maintaining patients eligible for transplantation. Lastly, we explore emerging ablation modalities, comparing them with the current standard, radiofrequency ablation. In conclusion, this comprehensive review provides insights into recent trends and future prospects in the surgical management of HCC, highlighting areas that require further investigation.

Background. To investigate the impact of intrapatient variability (IPV) in the levels of immunosuppressant drugs on health outcomes after liver transplantation. Methods. A comprehensive systematic review and meta-analysis were conducted, examining literature from MEDLINE/PubMed, Embase, Web of Science, Cochrane Reviews, and Cochrane CENTRAL. Results. The analysis focused on acute rejection, graft survival, acute kidney injury, and cancer risk as health outcomes. Of 2901 articles screened, 10 met the inclusion criteria. The results indicate a 19% reduction in the risk of acute rejection in patients with lower IPV (RR = 0.81; 95% confidence interval, 0.66-0.99), although 6 studies found no significant association between high IPV and acute rejection. Contrasting results were observed for graft survival, with 1 study indicating worse outcomes for high IPV, whereas another reported no significant difference. High IPV was consistently associated with acute kidney injury across 3 studies. One study suggested a link between high IPV and hepatocellular carcinoma, although a meta-analysis for these outcomes was not feasible. Conclusions. These findings point to a marginal but statistically significant association between high IPV and an increased risk of acute rejection, highlighting the importance of precise management of immunosuppressive drugs in liver transplant recipients to enhance patient outcomes. Export

Background/Objectives: Hepatocellular carcinoma (HCC) therapies are limited by poor response, rapid resistance, and recurrence of aggressive disease. Sorafenib, a multi-tyrosine kinase inhibitor, can trigger β-catenin stabilization and activation, contributing to resistance. Overexpression of the chemokine receptor CXCR6 and its ligand CXCL16 and hyperactivation are implicated in HCC progression and β-catenin stabilization. We hypothesized that SBI-457, a small-molecule CXCR6 antagonist we developed, could disrupt CXCR6/β-catenin crosstalk and enhance sorafenib sensitivity. Methods: We tested SBI-457 alone and in combination with sorafenib in SK-Hep-1 xenograft models and a panel of human HCC cell lines. Tumor burden, β-catenin activation, and CXCR6 expression were assessed by tumor volume measurements, immunohistochemistry, Western blotting, and immunofluorescence. Soluble CXCL16 levels were quantified by ELISA, and cell death responses were evaluated using MTT assays. Results: In vivo, SBI-457 combined with sorafenib reduced normalized tumor volume by 55% compared to vehicle controls, modestly exceeding monotherapy effects, and attenuated sorafenib-induced β-catenin upregulation. In vitro, SBI-457 blocked nuclear accumulation of β-catenin and reversed sorafenib-induced increases in β-catenin levels. Enhanced cell death was observed in specific “responder” HCC cell lines (Hep-3B, SNU-398, JHH-5), which correlated with high intracellular β-catenin, secretion of soluble CXCL16, and expression of a high molecular weight form of CXCR6. In contrast, “non-responder” cell lines with conventional CXCR6 expression and low CXCL16 secretion showed no enhanced cell death response. Conclusions: CXCR6 antagonism with SBI-457 can modulate β-catenin activation and may help overcome sorafenib resistance in selected HCC models. These findings support further development of CXCR6 antagonists as single agents or combination therapies to improve treatment outcomes in HCC.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with poor patient outcomes largely attributable to late diagnosis and the frequent development of therapeutic resistance. Although advances in chemotherapy, targeted therapies, immunotherapy, and combination regimens have improved treatment options, durable clinical responses remain limited. This review synthesizes current evidence on the role of β-catenin signaling in HCC progression and therapeutic resistance, emphasizing the molecular mechanisms underlying aberrant pathway activation and its interactions with other oncogenic signaling networks. The review examines how constitutive β-catenin activation promotes tumor growth, cancer stem cell maintenance, metabolic reprogramming, immune evasion, and resistance to chemotherapy, targeted therapies, and immune checkpoint inhibitors. In addition, emerging therapeutic strategies targeting β-catenin are discussed, including inhibition of β-catenin transcriptional activity, modulation of upstream Wnt signaling, direct suppression of CTNNB1 expression using nucleic acid-based approaches, and interventions targeting the immune and metabolic consequences of pathway activation. Collectively, the evidence identifies β-catenin as a central mediator of HCC progression and treatment resistance while highlighting its potential as a therapeutic target. A deeper understanding of β-catenin-driven mechanisms may facilitate the development of more effective therapeutic strategies and improve clinical outcomes for patients with HCC.

Hepatocellular carcinoma (HCC) commonly arises in metabolic dysfunction-associated steatohepatitis (MASH), alcohol-related liver disease (ALD), and metabolic dysfunction-associated ALD (MetALD), yet how zonal metabolic programs govern tumor lineage and immune responses remains unclear. Here, using complementary murine models of steatohepatitis-associated hepatocarcinogenesis, we show that CTNNB1-mutant MASH-HCC originates from periportal and midlobular hepatocytes through perivenous reprogramming. This transition is characterized by β-catenin activation, loss of periportal metabolic functions, and induction of the immunosuppressive IDO1-kynurenine-AhR axis. In contrast, ethanol exposure suppresses perivenous xenobiotic programs, destabilizes the β-catenin/AhR/CAR axis, and increases tumor heterogeneity by generating both progenitor/biliary- and hepatocyte-derived MetALD-HCC that remain sensitive to anti-programmed death-1 (aPD1) therapy. Pharmacologic AhR inhibition or hepatocyte-specific β-catenin deletion reduces MASH-HCC burden and restores sensitivity to aPD1 treatment. Together, these findings identify AhR as a central mediator of β-catenin-driven tumor immunosuppression and a potential therapeutic target in CTNNB1-mutant HCC, highlighting context-dependent mechanisms of immune escape in alcohol-associated HCC.