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Hepatocellular carcinoma (HCC) is one of the most lethal cancer types with insufficient approved therapies, among which lenvatinib is a newly approved multi‐targeted tyrosine kinase inhibitor for frontline advanced HCC treatment. However, resistance to lenvatinib has been reported in HCC treatment recently, which limits the clinical benefits of lenvatinib. This study aims to investigate the underlying mechanism of lenvatinib resistance and explore the potential drug to improve the treatment for lenvatinib‐resistant (LR) HCC. Here, we developed two human LR HCC cell lines by culturing with long‐term exposure to lenvatinib. Results showed that the vascular endothelial growth factor receptors (VEGFR)2 expression and its downstream RAS/MEK/ERK signalling were obviously up‐regulated in LR HCC cells, whereas the expression of VEGFR1, VEGFR3, FGFR1‐4 and PDGFRα/β showed no difference. Furthermore, ETS‐1 was identified to be responsible for VEGFR2 mediated lenvatinib resistance. The cell models were further used to explore the potential strategies for restoration of sensitivity of lenvatinib. Sophoridine, an alkaloid extraction, inhibited the proliferation, colony formation, cell migration and increased apoptosis of LR HCC cells. In vivo and in vitro results showed Sophoridine could further sensitize the therapeutic of lenvatinib against LR HCC. Mechanism studies revealed that Sophoridine decreased ETS‐1 expression to down‐regulate VEGFR2 expression along with downstream RAS/MEK/ERK axis in LR HCC cells. Hence, our study revealed that up‐regulated VEGFR2 expression could be a predicator of the resistance of lenvatinib treatment against HCC and provided a potential candidate to restore the sensitivity of lenvatinib for HCC treatment.

Background N 4 -acetylcytidine (ac 4 C) is an emerging epitranscriptomic modification that regulates mRNA stability and translation, yet its biological and clinical relevance in cholangiocarcinoma (CCA) remains unclear. Methods We integrated single-cell RNA sequencing (scRNA-seq) and multi-cohort bulk transcriptomic data to systematically profile ac 4 C-related genes (acRGs) in CCA. Using UCell scoring and CellChat analysis, we assessed ac 4 C activity and intercellular communication within the tumor microenvironment (TME). A comprehensive machine learning framework combining 117 model algorithms was implemented to construct an ac 4 C-related gene signature (acRGS) for prognostic prediction. Immune contexture, causal inference, and in vivo validation were subsequently performed to elucidate functional relevance. Results Single-cell analysis revealed that malignant and myeloid populations exhibited the highest ac 4 C activity and denser ligand-receptor crosstalk. The derived 11-gene acRGS robustly stratified patients into prognostic groups across independent cohorts. High-risk tumors showed elevated checkpoint expression but markedly reduced immune and stromal infiltration, indicating an immune-exhausted yet poorly inflamed TME. Mendelian randomization identified S100A13 and ASPH as causal ac 4 C-linked risk genes for CCA. Functional experiments confirmed that S100A13 overexpression significantly enhanced tumor growth and proliferation in vivo. Conclusions Our integrative framework delineates the transcriptional and immunological consequences of ac 4 C modification in CCA and identifies S100A13 as a novel ac 4 C-associated oncogene. The acRGS provides a clinically relevant tool for prognostic assessment and mechanistic insight into RNA acetylation-driven tumor progression.

Background In this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC. Methods Integrated analysis, cox regression and the least absolute shrinkage and selection operator (LASSO) method of 104 ferroptosis- and iron metabolism-related genes and HCC-related RNA sequencing were performed to identify HCC-related ferroptosis and iron metabolism genes. Results Four genes (ABCB6, FLVCR1, SLC48A1 and SLC7A11) were identified to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort ( P  < 0.001, HR = 0.27) and test cohort (P < 0.001, HR = 0.27). The diagnostic models successfully distinguished HCC from normal samples and proliferative nodule samples. Compared with low-risk groups, high-risk groups had higher TMB; higher fractions of macrophages, follicular helper T cells, memory B cells, and neutrophils; and exhibited higher expression of CD83, B7H3, OX40 and CD134L. As an inducer of ferroptosis, erastin inhibited HCC cell proliferation and progression, and it was showed to affect Th17 cell differentiation and IL-17 signaling pathway through bioinformatics analysis, indicating it a potential agent of cancer immunotherapy. Conclusions The prognostic and diagnostic models based on the four genes indicated superior diagnostic and predictive performance, indicating new possibilities for individualized treatment of HCC patients. 6i5hPu8DcyHvJLmULV1p7n Video Abstract Graphical abstract

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic and incurable inflammatory diseases involving the gastrointestinal tract. In this study, we investigated the anti-inflammatory effects of triptolide in a dextran sulfate sodium (DSS)-induced mouse colitis model and LPS-activated macrophages and explored the specific molecular mechanism(s). In mice, triptolide treatment showed significant relief and protection against colitis, and it markedly reduced the inflammatory responses of human monocytes and mouse macrophages. Pharmacological analysis and weighted gene co-expression network analysis (WGCNA) suggested that PDE4B may be an important potential targeting molecule for IBD. Exploration of the specific mechanism of action indicated that triptolide reduced the production of ROS, inhibited macrophage infiltration and M1-type polarization by activating the NRF2/HO-1 signaling pathway, and inhibited the PDE4B/AKT/NF- B signaling cascade, which may help weaken the intestinal inflammatory response. Our findings laid a theoretical foundation for triptolide as a treatment for IBD and revealed PDE4B as a target molecule, thus providing new ideas for the treatment of IBD.

The tumor microenvironment (TME) is a complex and dynamic ecosystem that plays a critical role in cancer progression. It comprises various cell types, including immune cells, tumor cells, and stromal cells. Among these, cancer-associated fibroblasts (CAFs) represent a heterogeneous population with diverse origins, phenotypes, and functions. Activated CAFs secrete multiple factors that promote tumor growth, migration, angiogenesis, and contribute to chemoresistance. Additionally, CAFs secrete extracellular matrix (ECM) components, such as collagen, which form a physical barrier that hinders the penetration of chemotherapeutic and immunotherapeutic agents. This ECM also influences immune cell infiltration, impeding their ability to effectively target tumor cells. As a result, modulating the activity of CAFs has emerged as a promising strategy to enhance the efficacy of tumor immunotherapy. Nano-delivery systems, constructed from various nanomaterials with high targeting specificity and biocompatibility, offer a compelling approach to deliver therapeutic agents or immunomodulatory factors directly to CAFs. This modulation can alter CAF function, reduce their tumor-promoting effects, and thereby improve the outcomes of immunotherapy. This review provides an in-depth exploration of the origins, functions, and interactions of CAFs within the TME, particularly in the context of immune suppression. Furthermore, it discusses the potential applications of functional nanocarrifers in modulating CAFs and enhancing the effectiveness of tumor immunotherapy, highlighting the significant progress and potential of nanotechnology in this area. Graphical Abstract

DNA nanotechnology offers a powerful alternative in biomedical areas yet a simple and general strategy to engineer DNA-based nanomedicine bearing high and adjustable drug-loading capacity and stability remains challenging. Herein, we report that it is a ubiquitous property for plain DNA (except for guanine-rich sequences) to assemble with the widely used anticancer drug, doxorubicin hydrochloride (DOX), into well-defined nanospheres via thermal annealing, which circumvents additional adjuvants (e.g., metal ions) or chemical modifications of DNA (e.g., hydrophobic conjugation). Experimental results and molecular dynamics simulation reveal that shape remolding is a result of heat-promoted intra-particle interactions. We demonstrate that the nanospheres display high DOX-loading capacity and feasible size controllability, and the generality of this approach is also established with diverse functional cationic aromatics (drugs, fluorescent dyes and aggregation-induced emission luminogens). Finally, we construct a carrier-free nanomedicine by assembling DOX with a therapeutic antisense oligonucleotide, and the combined therapeutic performance is demonstrated in vitro and in vivo. Graphical Abstract

Cancer stem cells (CSCs) are a subpopulation of cells within tumors that are believed to possess pluripotent properties and thought to be responsible for tumor initiation, progression, relapse and metastasis. Cytoplasmic polyadenylation element-binding protein 1 (CPEB1), a sequence-specific RNA-binding protein that regulates mRNA polyadenylation and translation, has been linked to cancer progression and metastasis. However, the involvement of CPEB1 in hepatocellular carcinoma (HCC) remains unclear. In this study, we have demonstrated that CPEB1 directly regulates sirtuin 1 (SIRT1) mRNA to mediate cancer stemness in HCC. Cancer stemness was analyzed by self-renewal ability, chemoresistance, metastasis, expression of stemness-related genes and CSC marker-positive cell populations. The results indicate that CPEB1 is downregulated in HCC. Overexpression of CPEB1 dramatically reduced HCC cell stemness, whereas silencing CPEB1 enhances it. Using site-directed mutagenesis, a luciferase reporter assay, and immunoprecipitation, we found that CPEB1 could directly target the 3′-UTR of SIRT1, control poly(A) tail length and suppress its translation to mediate cancer stemness in vitro and in vivo. Overall, our findings suggest that the negative regulation between CPEB1 and SIRT1 contributes to the suppression of cancer stemness in HCC. CPEB1 may have potential as a therapeutic target in HCC.

Objectives: This study aims to develop and validate a prognostic risk model by integrating pathomics features with clinical variables to predict disease-free survival (DFS) in patients with gastric cancer (GC). Methods: Patients with GC who were pathologically diagnosed and subsequently treated with curative gastrectomy and D2 lymphadenectomy at the Fifth Affiliated Hospital of Wenzhou Medical University between January 2017 and April 2023 were retrospectively enrolled and assigned to a training cohort (n = 275) and an independent validation cohort (n = 118). Pathomics features were extracted from pathological images, and LASSO-Cox regression was used to identify pathomics features significantly associated with DFS. The selected pathomics features were integrated with clinical factors to create a prognostic model. Predictive accuracy was evaluated using time-dependent ROC analysis, and the model’s performance was compared with the clinic-only and pathomics-only models. A nomogram was constructed to provide individualized DFS predictions. Results: A total of 16 pathomics features were selected, and the cut-off for the pathomics scores was set at 0.27. High-risk patients exhibited significantly worse DFS compared to low-risk patients in both the training cohort (HR = 4.57, 95% CI: 3.118–6.697, p < 0.0001) and the validation cohort (HR = 2.264, 95% CI: 1.255–4.083, p < 0.0001). The clinic–pathomics model demonstrated strong predictive performance in both cohorts, with AUCs for 1-, 3-, and 5-year survival of 0.832, 0.821, and 0.851 in the training cohort, and 0.671, 0.702, and 0.682 in the validation cohort. The nomogram, incorporating the pathomics score, T stage, differentiation degree, and ECOG performance status, showed high calibration accuracy, as confirmed by calibration plots, and outperformed both the clinic-only and pathomics-only models in decision curve analysis. Conclusions: A clinic–pathomics model integrating pathomics features with clinical data provides a reliable tool for DFS prediction in patients with GC, which facilitates individualized DFS predictions and personalized treatment strategies.

Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. With the approval of multiple first- and second-line agents, especially the combination therapies based on immune checkpoint inhibitor (ICI) regimens, the landscape of systemic therapy for advanced HCC (aHCC) is more diverse than ever before. The efficacy of current systemic therapies shows great heterogeneity in patients with aHCC, thereby identifying biomarkers for response prediction and patient stratification has become an urgent need. The main biomarkers for systemic therapy in hepatocellular carcinoma are derived from peripheral blood, tissues, and imaging. Currently, the understanding of the clinical response to systemic therapy indicates unequivocally that a single biomarker cannot be used to identify patients who are likely to benefit from these treatments. In this review, we provide an integrated landscape of the recent development in molecular targeted therapies and ICIs-based therapies, especially focusing on the role of clinically applicable predictive biomarkers. Additionally, we further highlight the latest advancements in biomarker-driven therapies, including targeted treatments, adoptive cell therapies, and bispecific antibodies.