Background and Aims: Liver HCC is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature. Approach and Results: Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine, and sphingolipid derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting lysophosphatidylcholine acyltransferase 1 (LPCAT1) and ceramide synthase 5 (CERS5) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy. Conclusions: In conclusion, our study elucidates the metabolic reprogramming nature of lipid metabolism in HCC, identifies prognostic markers and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.

Hepatocellular carcinoma (HCC) remains a critical global health concern, particularly in regions with high endemicity of hepatitis B, hepatitis C, and non-alcoholic fatty liver disease. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a promising therapeutic strategy for advanced HCC. Despite encouraging results, primary and acquired resistance to ICIs continues to pose significant challenges in clinical practice. Recent research has identified tumor-associated macrophages (TAMs) as key contributors to immune evasion and ICI resistance in HCC, primarily through polarization to the M2 phenotype. M2-polarized TAMs secrete a range of immunosuppressive cytokines that inhibit T cell activation and promote tumor progression through processes such as angiogenesis and epithelial-mesenchymal transition. These mechanisms compromise the efficacy of ICIs and facilitate tumor expansion and metastasis. This review summarizes the role of TAM-related signaling pathways in driving immune evasion and ICI resistance in HCC, with particular emphasis on the contribution of TAM surface receptors and chemokines in immune suppression. Additionally, the review highlights emerging insights into TAM metabolic reprogramming and transcriptional regulation, which have been closely linked to ICI resistance. Furthermore, we explore promising therapeutic strategies targeting TAMs and their associated signaling pathways to enhance ICI efficacy in HCC. Integrating these novel approaches could potentially overcome TAM-driven immune evasion and ICI resistance, boosting the efficacy of immunotherapy and improving patient prognosis in HCC.

Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease characterized by fatty infiltration of the liver. In recent years, the MAFLD incidence rate has risen and emerged as a serious public health concern. MAFLD typically progresses from the initial hepatocyte steatosis to steatohepatitis and then gradually advances to liver fibrosis, which may ultimately lead to cirrhosis and carcinogenesis. However, the potential evolutionary mechanisms still need to be clarified. Recent studies have shown that nucleotide methylation, which was directly associated with MAFLD’s inflammatory grading, lipid synthesis, and oxidative stress, plays a crucial role in the occurrence and progression of MAFLD. In this review, we highlight the regulatory function and associated mechanisms of nucleotide methylation modification in the progress of MAFLD, with a particular emphasis on its regulatory role in the inflammation of MAFLD, including the regulation of inflammation-related immune and metabolic microenvironment. Additionally, we summarize the potential value of nucleotide methylation in the diagnosis and treatment of MAFLD, intending to provide references for the future investigation of MAFLD.

The integration of Hepatitis B Virus (HBV) is now known to be closely associated with the occurrence of liver cancer and can impact the functionality of liver cells through multiple dimensions. However, despite the detailed understanding of the characteristics of HBV integration and the mechanisms involved, the subsequent effects on cellular function are still poorly understood in current research. This study first systematically discusses the relationship between HBV integration and the occurrence of liver cancer, and then analyzes the status of the viral genome produced by HBV replication, highlighting the close relationship and structure between double-stranded linear (DSL)-HBV DNA and the occurrence of viral integration. The integration of DSL-HBV DNA leads to a certain preference for HBV integration itself. Additionally, exploration of HBV integration hotspots reveals obvious hotspot areas of HBV integration on the human genome. Virus integration in these hotspot areas is often associated with the occurrence and development of liver cancer, and it has been determined that HBV integration can promote the occurrence of cancer by inducing genome instability and other aspects. Furthermore, a comprehensive study of viral integration explored the mechanisms of viral integration and the internal integration mode, discovering that HBV integration may form extrachromosomal DNA (ecDNA), which exists outside the chromosome and can integrate into the chromosome under certain conditions. The prospect of HBV integration as a biomarker was also probed, with the expectation that combining HBV integration research with CRISPR technology will vigorously promote the progress of HBV integration research in the future. In summary, exploring the characteristics and mechanisms in HBV integration holds significant importance for an in-depth comprehension of viral integration.

Background: Curcumol, a bioactive sesquiterpenoid extracted from traditional Chinese medicine (TCM), has demonstrated potential in overcoming tumor drug resistance. However, its mechanisms in reversing drug resistance, particularly in hepatocellular carcinoma (HCC) resistant to sorafenib, are not yet fully elucidated. This study aims to explore the molecular mechanisms by which curcumol reverses sorafenib resistance in HCC using a combination of network pharmacology, molecular docking, and in vivo and in vitro experiments.Methods: We identified curcumol targets and genes associated with sorafenib-resistant HCC, resulting in a set of overlapping targets. These intersection targets underwent enrichment analysis using DAVID, and a protein-protein interaction (PPI) network was constructed via the STRING database and Cytoscape. Molecular docking confirmed the binding of curcumol to core targets. In vitro assays, including CCK-8, colony formation assay, apoptosis detection, wound healing, and Transwell assays, evaluated curcumol’s effects on sorafenib-resistant HCC cells. Western blotting assessed the impact on PI3K/AKT and JAK/STAT3 signaling pathways. Additionally, a sorafenib-resistant HCC xenograft mouse model was established to observe the in vivo efficacy of curcumol combined with sorafenib.Results: We identified 117 potential targets for curcumol in reversing sorafenib resistance in HCC. Among them, five core targets—ALB, STAT3, HSP90AA1, HSP90AB1, and SRC—showed strong binding affinity with curcumol. KEGG pathway analysis of the intersecting genes highlighted significant involvement of the PI3K/AKT, JAK/STAT3, Ras, Rap1, HIF-1, FoxO, and mTOR signaling pathways. In vitro experiments revealed that curcumol significantly enhanced the sensitivity of sorafenib-resistant HCC cells to sorafenib, inhibiting cell proliferation, invasion, and migration while promoting apoptosis. In vivo studies further confirmed that curcumol combined with sorafenib effectively inhibited tumor growth in sorafenib-resistant HCC models.Conclusion: This study provides compelling evidence that curcumol can reverse sorafenib resistance in HCC by modulating multiple signaling pathways, including PI3K/AKT and JAK/STAT3 pathways. Our findings suggest that curcumol holds promise as a novel therapeutic agent for overcoming drug resistance in HCC, offering a new avenue for clinical intervention.

Background Papillary thyroid cancer (PTC) is frequently associated with inflammation and lymph node (LN) metastasis. Single-cell RNA sequencing (scRNA-seq) can uncover rare sub-populations of cells and explore functional heterogeneity of tissue microenvironments. Here, through scRNA-seq analysis of a metastatic PTC (PTC-M) and its adjacent normal tissues as well as a PTC tumor without metastasis, we identified the heterogeneity of macrophages, dendritic cells (DCs), and T cells in the PTC-M sample, implying the role of the immunosuppressive components in the development and metastasis of PTC.Results Our results demonstrated that alternatively activated (M2) macrophages, conventional-type 2 dendritic cells (cDC2s), and regulatory T cells (Tregs) were associated with greater lymph node metastases and more advanced stages, whereas monocytes and B cells could play an anti-tumor role. Notably, a cluster of tumor-associated LAMP3⁺CCL22⁺ DC2 cells expressed diverse immune-related ligands and exhibited the potential to recruit CD4⁺ T cells by cell-cell communications in the microenvironment.Conclusion In the present study, we provided insights into the immune landscape at a single-cell level and expanded potential therapeutic strategies for PTC with metastasis. The results supported the theory that certain clusters of myeloid cells and Tregs participated in modulating the tumor-associated environment and facilitating tumor progression or metastasis.