Clinical and Molecular Hepatology最新文献

Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently gained attention as a risk factor for primary liver cancer and extrahepatic cancers. Increasing evidence shows that MASLD creates a fibrotic, immunosuppressive tumor microenvironment that supports metastatic growth, making it a risk factor for liver metastasis from extrahepatic tumors, such as colorectal cancer. In steatotic liver, tumor-stromal interactions promote colorectal liver metastasis through several mechanisms, including extracellular vesicles enriched with oncogenic microRNAs, hyaluronan synthase 2-mediated hyaluronic acid production by activated hepatic stellate cells and cancer-associated fibroblasts, M2-polarized tumor-associated macrophage infiltration, and Yes-associated protein-dependent tumor signaling. In this review, we summarize key pathways involved in a pre- and pro-metastatic niche in the liver, such as extracellular vesicle-mediated intercellular communication, feed-forward loops between tumor cells and stromal fibroblasts, and hyaluronic acid-induced extracellular matrix remodeling and immune cell modulation, all of which impair antitumor immunity and promote immune escape. We also discuss how targeting hyaluronic acid synthesis, interleukin-1 signaling, or CXCR2 can restore antitumor immunity and improve responses to programmed cell death protein-1 blockade. These therapeutic approaches may offer promising benefits for patients with colorectal cancer liver metastasis.

Background /aims: Recurrence is a major factor limiting the long-term survival of patients with intrahepatic cholangiocarcinoma (ICC). The molecular characteristics and potential therapeutic targets in ICC remain largely undefined.

Methods: Following our previous whole-exome sequencing study, we performed targeted sequencing, Sanger sequencing, and quantitative PCR to assess all coding exons and copy number variations of LATS2 in 400 primary ICC samples. Kaplan-Meier survival curves were used to assess the impact of LATS2 mutation, copy number loss, and low expression levels on recurrence-free survival and overall survival in ICC patients. In addition, we investigated the functional role and underlying mechanisms of LATS2 variation in ICC tumor progression and resistance to anti-PD1 therapy.

Results: Among a total of 400 ICC cases, the overall frequencies of LATS2 somatic mutation and copy number loss were 3% (12/400) and 34% (136/400), respectively. Both types of variation were correlated with decreased LATS2 protein expression, increased tumor recurrence, and poor overall survival. Biofunctional investigations revealed a tumor-suppressor role of LATS2. Inactivation of LATS2 suppressed the Hippo signaling pathway, leading to aberrant activation of YAP, which upregulated PD-L1 expression and CCL2 secretion, suppressed CD8+ T cell infiltration, and enhanced recruitment of M2-like macrophages, thereby promoting immune evasion, tumor progression, and resistance to anti-PD-1 therapy.

Conclusions: Our study reveals a pivotal clinical association and mechanistic role of LATS2-inactivating variation in ICC, which may serve as a useful biomarker for precision therapy.

Hepatitis B flare is a common complication of Chronic Hepatitis B (CHB) and is defined as an increase in HBV viral load associated with abnormal alanine aminotransferases (ALT), the consensus being an ALT≥5xupper limit of normal. The immunopathogenesis is related to induction of inflammatory cells and cytokines by the rise in HBV DNA. There are multiple causes of flares, and they carry the risk of progression to hepatic decompensation and acute-on-chronic liver failure (ACLF) with its associated mortality, potentially requiring liver transplantation. Initial assessment should be exclusion of other causes of liver dysfunction, determine severity, and prognosis. General prognostic models of ACLF are useful but the COSSH-ACLF II score is specific for HBV. Initiation of nucleos(t)ide analogues early is crucial and even in severe HBV flares reduces mortality by 73.6%. Once jaundice and coagulopathy occur, salvage by antivirals is challenging, and such patients should be considered for liver transplantation. However, many patients may not be suitable for transplant or may not have available donor livers as is common in Asia. Recently, there has been increasing evidence of benefit with adjunctive therapies such as corticosteroids and plasma exchange, but this needs to be balanced with the risks and should be considered as rescue therapies in severe HBV flares or ACLF. Liver transplant is the ultimate intervention when these other strategies fail to rescue patients. In summary, HBV flares are clinically serious events that can lead to hepatic decompensation and ACLF but strategies for rescue should be considered before liver transplantation.

Background/aims: Lenvatinib resistance and immune exclusion limit outcomes in HCC. We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and PD-1 blockade.

Methods: We established LS/LR HCC models and employed multi-omics (proteomics/RNA-seq), ChIP, luciferase, and RIP assays to map HKDC1 regulation. Tumor immunity was profiled by scRNA-seq, mIHC, and flow cytometry. SPD + lenvatinib efficacy was tested in cell lines, patient-derived organoids/xenografts. Tested therapy effect in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion; and analyzed a postoperative cohort (n = 40) treated with lenvatinib + PD-1.

Results: HKDC1, upregulated in LR HCC, was transcriptionally activated by USF1 and promoted SMS-mediated polyamine rewiring. This impaired CD8⁺ T-cell metabolism, reversible by HKDC1 knockdown or spermidine (SPD). SPD synergized with lenvatinib, triggering autophagy and suppressing tumor growth in vitro and in vivo. High HKDC1 predicted poor response and survival in patients receiving lenvatinib + aPD-1.

Conclusions: A USF1/HKDC1/SMS axis couples polyamine metabolism to immune dysfunction and lenvatinib resistance. HKDC1 is a predictive biomarker and therapeutic node and support polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.