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Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. While age-standardized incidence and mortality have declined in some regions, the overall global burden continues to increase because of population aging and persistent etiologic factors. Curative options are limited to selected patients, and systemic therapies provide modest long-term benefit. Beyond its canonical role in calcium-phosphate homeostasis, vitamin D signals through the nuclear vitamin D receptor (VDR) to modulate immunity, oxidative stress, fibrosis, and cellular metabolism. In HCC, this axis is frequently dysregulated, including downregulation of CYP2R1, reduced CYP27B1 activity, upregulation of CYP24A1, and VDR dysfunction, which together blunt the antitumor actions of vitamin D and are linked to inflammation, aberrant lipogenesis, and immune evasion. Here, we summarize mechanisms by which vitamin D impacts key oncogenic pathways in HCC, including PI3K/AKT/mTOR, IL-6/STAT3, NF-κB, and TGF-β/SMAD, and highlight downstream nodes such as SREBP-1 and TXNIP as potential therapeutic targets. We also discuss emerging strategies to restore vitamin D signaling, such as CYP24A1 inhibition, next-generation vitamin D analogs, and VDR-biased agonists, to facilitate clinical translation and drug development. [Image: see text] Vitamin D metabolism and signaling are frequently dysregulated in hepatocellular carcinoma (HCC), including CYP2R1 downregulation, CYP27B1 suppression, CYP24A1 overactivation, and VDR silencing. Vitamin D exerts antitumor effects in HCC through anti-inflammatory, antioxidant, antifibrotic, and metabolic reprogramming pathways. SREBP-1 and TXNIP are identified as novel vitamin D–related molecular targets with potential therapeutic value in HCC. Vitamin D analogs, CYP24A1 inhibitors, and VDR-biased agonists represent promising strategies for overcoming resistance and optimizing HCC treatment.
Gastric cancer (GC) remains a leading cause of cancer-related mortality globally and is characterized by significant inter- and intra-tumoral heterogeneity, which poses major challenges to effective treatment. Although traditional "one-size-fits-all" chemotherapy regimens have improved outcomes, the prognosis for advanced disease remains poor, necessitating a paradigm shift towards personalized medicine. This review provides a comprehensive synthesis of the current landscape of precision oncology in GC. We systematically analyze the clinical implications of major molecular classification systems, particularly The Cancer Genome Atlas (TCGA) subtypes (EBV-positive, MSI-H, GS, and CIN), and their role in guiding therapeutic stratification. The integration of molecular profiling has revolutionized the management of GC. We discuss the evolution of targeted therapies, ranging from established standards, like HER2 inhibition, to emerging targets, including Claudin18.2 and FGFR2, highlighting their potential of overcoming resistance mechanisms. Furthermore, we evaluate the efficacy of immune checkpoint inhibitors (PD-1/PD-L1 blockade), specifically in the context of high microsatellite instability (MSI-H) and EBV-positive subtypes, where these have demonstrated robust antitumor activity. Beyond tissue-based markers, this article also explores the expanding role of liquid biopsies, including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), as non-invasive tools for real-time monitoring of disease progression and therapeutic response. Precision oncology represents a transformative approach in GC, moving beyond histology to a molecularly driven treatment framework. However, realizing its full potential requires addressing challenges related to tumor heterogeneity and drug resistance. Future research must focus on validating novel biomarkers and developing synergistic combination strategies to further improve patient survival.
Dysregulated cholesterol metabolism has emerged as a crucial driver of hepatocellular carcinoma (HCC) progression and immunotherapy resistance. This study aimed to delineate the single-cell landscape of cholesterol metabolism in HCC and identify key molecular determinants linking metabolic reprogramming to tumor aggressiveness and immune evasion. An integrative multi-omics approach combining bulk and single-cell RNA sequencing from multiple-center cohorts was employed. Metabolic activity scoring, high-dimensional weighted gene co-expression network analysis (hdWGCNA), and a five-model integrated machine learning strategy were applied to identify hub genes associated with cholesterol metabolism. Functional assays, including genetic silencing, metabolic profiling, and orthotopic mouse models with anti-PD-1 and FDPS inhibitor (alendronic acid), were used to validate mechanistic and therapeutic relevance. Cholesterol metabolic activity was markedly elevated in HCC tumors and immune checkpoint blockade (ICB) non-responders, with pronounced intratumoral heterogeneity across malignant cell subpopulations. The enzyme Farnesyl Diphosphate Synthase (FDPS) emerged as a pivotal regulator, promoting tumor cell cholesterol metabolism and proliferation. Further functional experiments demonstrated that targeting FDPS suppressed tumor growth, reduced intracellular cholesterol levels and significantly enhanced anti-PD-1 efficacy in vivo, accompanied by increased lymphoid immune infiltration. Our findings establish FDPS-driven cholesterol metabolic reprogramming as a key mechanism of HCC malignancy and immunotherapy resistance. Targeting FDPS offers a promising strategy to potentiate immune checkpoint therapy and reshape metabolic vulnerabilities in liver cancer. The online version contains supplementary material available at 10.1007/s13402-026-01177-7.
Hepatocellular carcinoma (HCC), a malignancy driven by multifaceted genetic and epigenetic mechanisms, is the leading cause of cancer deaths worldwide. Long non-coding RNAs (lncRNAs), particularly super-enhancer-associated lncRNAs (SE-lncRNAs), have emerged as critical regulators of tumorigenesis. In our study, we explored the expression of super-enhancer (SE)-associated lncRNA (seRNA) in HCC and investigated the role of a SE-lncRNA, HDAC11-AS1, in the progression of HCC. HCC-specific SE-lncRNAs were identified by H3K27ac ChIP-seq data (from ENCODE database) of Huh7, HepG2, and normal liver tissues using the ROSE algorithm. HDAC11-AS1 overexpression was validated in 36 pairs of HCC patient samples and adjacent tissues. The effects of HDAC11-AS1 on HCC proliferation and migration was analyzed in vitro and in vivo by overexpression or knockdown of HDAC11-AS1. Co-expression genes analysis of HDAC11-AS1, qPCR, western blot analysis and immunohistochemistry (IHC) were used to detect the regulation of Histone Deacetylase 11(HDAC11) and Nucleoporin 210 (NUP210).ChIA-PET data analysis, RNA pulldown and RNA immunoprecipitation (RIP) were used to explore the interaction between HDAC11-AS1 and tanscription factor (YY1)/cofactors (EP300 and SMC3). In this study, we identified HDAC11-AS1, a SE-lncRNA significantly overexpressed in HCC tissues and associated with poor prognosis. Downregulation of HDAC1-AS1 suppressed proliferation and migration of HCC in vitro and in vivo. Mechanistically, HDAC11-AS1 as a pivotal SE-lncRNA driving HCC progression through transcriptional regulation of HDAC11 and NUP210 by interacting with transcription factor YY1 and cofactor (EP300 and SMC3) in stabilizing enhancer-promoter looping. Our findings reveal that HDAC11-AS1 functions as a molecular scaffold that stabilizes enhancer-promoter (E-P) looping, thereby promoting super-enhancer activity and the subsequent transcription of oncogenic drivers.
To develop a contrast-enhanced Magnetic Resonance Imaging (CEMRI)-based habitat radiomics model for predicting early treatment response to hepatic artery infusion chemotherapy with fluorouracil, leucovorin, and oxaliplatin (HAIC-FOLFOX) in patients with unresectable hepatocellular carcinoma (HCC) and elucidate the underlying biological mechanisms. Among 120 HCC patients who underwent HAIC treatment, habitat features were extracted by applying clustering algorithms to preoperative CEMRI to delineate intratumoral subregions with distinct enhancement characteristics. Least absolute shrinkage and selection operator (LASSO) and logistic regression were employed for feature selection to construct habitat, conventional radiomics, clinical, and combined models. Internal validation was performed using 1000 bootstrap resamples. In a separate cohort of 107 surgically resected HCC patients, the habitat model was applied for risk stratification, and correlations between habitat features and pathomorphological characteristics, as well as immunohistochemical (IHC) markers, were investigated. MRI images were categorized into three distinct habitats, and a predictive model was built from their proportional distribution. The habitat radiomics model achieved an area under the curve (AUC) of 0.868 (95% confidence interval (CI): 0.748–0.976), outperforming both conventional radiomics (AUC 0.849, 95% CI: 0.719–0.954) and clinical models (AUC 0.653, 95% CI: 0.497–0.802). The combined clinical-habitat model reached the highest AUC of 0.901 (95% CI: 0.795–0.989, P < 0.05). In the surgical cohort, low-risk habitat patients exhibited increased tumor necrosis/stromal components (elevated IntensityMin) and better differentiation (reduced CurvMean) (P < 0.05). Immunohistochemistry revealed higher microvessel density (CD34) and lower cancer stem cell marker expression (CK19, Glypican-3) in the low-risk group (P < 0.05). The CEMRI habitat radiomics model accurately predicts early HAIC treatment response, with risk stratification significantly correlated with pathomorphological and molecular characteristics.
High expression of the stress-response kinase GCN2 has been linked to poor survival in several cancers including cervical cancer, but its underlying biological roles remain incompletely understood. This study aimed to identify genes whose expression correlates with GCN2 in locally advanced cervical cancer and to use these associations to elucidate cellular functions that could contribute to aggressive disease behavior. Correlation analyses were performed between GCN2 expression and genome-wide mRNA profiles in a biobank of 291 patients with locally advanced cervical cancer. Gene ontology and pathway analyses were used to identify enriched biological processes, and functional assays were conducted to validate GCN2 involvement in selected pathways. GCN2 expression correlated not only with genes involved in cellular stress responses but also with those regulating mitosis and cell migration. Functional analyses confirmed that GCN2 activity promotes both proliferative and migratory capacities, revealing important cancer-relevant roles beyond its canonical function in translational control. Our findings demonstrate that elevated GCN2 levels support cellular functions that can contribute to tumor aggressiveness. These results suggest that GCN2 plays a direct role in malignant progression and may represent a potential biomarker or therapeutic target in locally advanced cervical cancer.
Gastric cancer (GC) characterized by profound cellular heterogeneity, with the diversity and interactions of cells within the tumor microenvironment (TME) playing critical roles in tumorigenesis, metastasis, and therapeutic response. However, the underlying mechanisms remain poorly understood. We aimed to elucidate the mechanisms of tumor progression and identify potential therapeutic targets by investigating cellular diversity and communication within the malignant epithelia and tumor microenvironment (TME) in GC. In-depth single-cell RNA sequencing (scRNA-seq) analyses were performed on 19 fresh samples from 12 GC patients, encompassing primary tumors, lymph nodes, and omental metastases. Subsequent bioinformatics analyses were conducted to characterize cellular heterogeneity, followed by experimental and clinical sample verifications to elucidate the molecular underpinnings of GC progression. Our study identified the cAMP response element modulator (CREM) as a key molecular driver for GC progression, which significant upregulation in malignant epithelial cells. CREM activation promotes aggressive tumor phenotypes and correlates with poorer patient outcomes by regulating the ITGA2B promoter and MAPK signaling pathway. Furthermore, we uncovered distinct heterogeneity in T cells and cancer-associated fibroblasts (CAFs) within the GC TME, revealing spatial disparities in immune microenvironments and cell-cell communication across tumor locations. By providing a comprehensive single-cell transcriptomic atlas of GC, this study highlights the pivotal role of CREM in GC progression. These findings deepen our understanding of GC pathogenesis and highlighted the key role of CREM in GC progression and advanced our understanding of GC pathogenesis and offer a foundation for developing targeted, personalized therapeutic strategies. The online version contains supplementary material available at 10.1007/s13402-026-01189-3.
Europe's Beating Cancer Plan is a substantial European Union (EU) investment into cancer prevention and treatment. Integration of genetic services towards personalised cancer prevention and care is a flagship of this plan. Genetic counselling is critical to this integration, facilitating informed patient decision making and improved clinical management. However, growing demands for genetic testing and concurrently increasing workforce shortages necessitate new strategies to equitably ensure sustainable access to counselling across the EU. This project aimed to inform future European activities by identifying priority European strategies for addressing common European genetic literacy, workforce, and reimbursement barriers to genetic counselling in cancer noted in prior work. A Delphi survey was conducted, with genetics, oncology, and patient stakeholders invited from all EU Member States. The response rate was 62% (124 total invitations). Over three phases, 77 participants - 28 geneticists; 14 oncologists; 18 genetic counsellors; 16 patient representatives; 1 otherwise qualified expert - rated 19 strategies according to their Importance, Urgency, and Feasibility and selected their top three priority strategies. Five strategies met pre-defined consensus thresholds and received a clear plurality of priority ratings: (1) EU-wide genetic counsellor recognition; (2) Including genetics expertise in oncology guideline creation; (3) Shared EU genetic counsellor registration/education with legal weight; (4) Mandatory counselling reimbursement when clinical guidelines are met; (5) Mandatory inclusion of genetics in oncology fellowship/continuing education. Results provide a roadmap of European actions which promise to sustainably improve access to genetic counselling in cancer care. Upcoming and ongoing EU projects promise to advance their implementation.
Current liver cancer research lacks reliable in vitro models that replicate tumor pathophysiology. This study establishes primary liver cancer (PLC) organoids from three major subtypes—hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular-cholangiocarcinoma (CHC)—to enable precise diagnostics and personalized therapies through comprehensive genomic profiling. Organoid cultures were generated from 11 PLC patients (5 HCC, 3 ICC, 3 CHC). Whole exome sequencing (WES), RNA-seq, and single-cell RNA-seq (scRNA-seq) were performed to analyze molecular differences. Drug screening targeting subtype-specific pathways was conducted to validate sequencing findings. WES and RNA-seq confirmed that organoids retained parental tumor genetics and heterogeneity, distinct from paracancerous tissues. scRNA-seq revealed distinct cell populations in HCC, ICC, and CHC organoids. Lipid metabolism was enriched in HCC organoids; tumor migration pathways were upregulated in ICC organoids; and mitochondrial function was enhanced in CHC organoids. Rosuvastatin inhibited HCC growth by targeting lipid metabolism, while pemigatinib reduced ICC malignancy by suppressing epithelial-mesenchymal transition. Regorafenib impaired mitochondrial function in CHC organoids, slowing progression. PLC-derived organoids serve as robust tools for biomarker discovery and drug screening. scRNA-seq elucidates inter- and intra-tumoral heterogeneity, offering insights for precision therapy in liver cancer. This model advances personalized treatment strategies for diverse PLC subtypes. The online version contains supplementary material available at 10.1007/s13402-026-01190-w.
Lactate and its associated modification, lactylation, have emerged as key regulators in influencing various cellular processes. This review explores the multifaceted roles of lactate and lactylation, highlighting their involvement in metabolic reprogramming and the modulation of key signaling pathways. Lactate and lactylation influence cell adhesion, protein degradation, and angiogenesis, contributing to tumor invasion and metastasis. These metabolic alterations maintain cancer stem cell characteristics, support tumorigenesis and resistance to therapy. Lactate and lactylation also facilitate immune evasion in the tumor microenvironment (TME) by modulating immune cell function and immune checkpoint pathways. The complex interplay between lactate, lactylation, and various cellular and immune mechanisms underscores the potential of targeting lactate-related pathways as a therapeutic strategy for cancer treatment. Herein, we provide a comprehensive overview of the current understanding of lactate and lactylation in cancer, offering insights into their roles as key drivers of tumor progression and metastasis. Not applicable.
Colorectal cancer (CRC) incidence and mortality rates are steadily on the rise, which brings significant public health concern worldwide, especially in China. Methyltransferase-like 7 A (METTL7A), a member of the methyltransferase-like family, is associated with various cancers including CRC. Notably, CRC progression is closely linked to metabolic reprogramming. However, its precise role in CRC, particularly metabolic reprogramming of CRC, remains unclear. METTL7A was identified as a pivotal gene closely associated with CRC by bioinformatics analyses. Through a series of cellular functional assays and several animal experiments, such as in situ tumor and spontaneous tumor in C57BL/6 mice, the role of METTL7A in the development of colorectal cancer was evaluated. Transcriptomics and proteomics were used to analyze the effects of METTL7A on the expression of numerous genes, especially those involved in metabolic processes including cholesterol synthesis pathway within CRC cells. Western-blotting, co-immunoprecipitation and immunofluorescence were used to elucidate the relationship of METTL7A and the cholesterol metabolic pathway. METTL7A exhibited low expression in CRC cell lines and CRC tissues and it was demonstrated to function as a tumor suppressor in CRC. Transcriptomic and proteomic analyses indicated that METTL7A affects genes related to the cholesterol metabolism pathway. METTL7A was further proven to directly bind to Sterol Regulatory Element-Binding Protein1 (SREBP1) and SREBP Cleavage-Activating Protein (SCAP), hindering the nuclear translocation of SREBP1 and thereby reducing intracellular cholesterol content. This study provides valuable insights into the role of METTL7A in CRC and its impact on metabolic reprogramming, particularly cholesterol synthesis, and identifies METTL7A as a potential therapeutic target of CRC.
Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with limited treatment options. Phosphoglycerate kinase 1 (PGK1), with both glycolytic and kinase activities, has been implicated in tumor progression, but its therapeutic potential in ESCC remains unclear. We assessed PGK1 by genetic knockdown and developed compd 25 − 4, a structure-based small-molecule inhibitor. Biochemical and cellular assays determined its activity against PGK1 and ESCC proliferation. Mechanisms were explored through cellular glycolysis analysis, autophagy assessment, reverse-phase protein array (RPPA) analysis, and signaling pathway characterization. PGK1 knockdown significantly impaired ESCC cell growth both in vitro and in vivo, supporting its role as a therapeutic target. Compd 25 − 4 inhibited PGK1 glycolytic activity with nanomolar potency (IC50 = 41 nM) and demonstrated > 5-fold selectivity toward EGFR-positive ESCC cells compared to EGFR-negative cells. Beyond glycolysis inhibition, compd 25 − 4 suppressed PGK1 kinase-mediated PRAS40 signaling and induced autophagy-dependent degradation of EGFR. This dual mechanism of action simultaneously disrupted cancer metabolism and EGFR-driven oncogenic signaling, leading to enhanced therapeutic efficacy. Our findings establish PGK1 as a promising therapeutic target in ESCC and identify compd 25 − 4 as a potent chemical tool for probing PGK1’s dual enzymatic functions. By concurrently blocking glycolysis and promoting autophagy-mediated EGFR degradation, targeting PGK1 provides a novel therapeutic strategy for EGFR-positive ESCC. The online version contains supplementary material available at 10.1007/s13402-026-01215-4.
The nervous system is increasingly recognized as a key regulator of the tumor microenvironment, engaging in bidirectional crosstalk with cancer cells through neurotransmitters, neuropeptides, and synaptic-like connections. Autonomic nerves modulate tumor progression: sympathetic signaling promotes growth, metastasis, and immune evasion via β-adrenergic receptor activation, while parasympathetic input exerts dual roles—driving gastric cancer yet protecting against colitis-associated colorectal cancer through the cholinergic anti-inflammatory pathway. Sensory nerves influence pain, angiogenesis, and immunity, with CGRP and substance P differentially regulating anti-tumor responses. Notably, functional neuro-glioma synapses have been identified, where neuronal glutamate release activates AMPA receptors on tumor cells, triggering Ca²⁺ influx and oncogenic signaling—providing a mechanistic basis for repurposing AMPA antagonists like perampanel. Glial cells, including Schwann cells and astrocytes, support perineural invasion, metabolic coupling, and therapy resistance via neurotrophic factor secretion and extracellular matrix remodeling. Tumor-derived signals reciprocally rewire neural circuits, enhancing innervation and neuroplasticity. Central brain regions, such as the paraventricular nucleus, integrate stress inputs to systemically regulate tumor immunity and metabolism through autonomic output. This dynamic interplay positions the nervous system as a master regulator of cancer biology. Targeting neural-tumor interactions—via β-blockers, neuromodulation, or bioelectronic medicine—offers novel therapeutic strategies. Future precision oncology approaches must consider tumor type, stage, and neural context to effectively disrupt this crosstalk and the emerging concept of cancer-induced nerve injury (CINI) as a novel mechanism of immunotherapy resistance. Not applicable
Colon adenocarcinoma (COAD) has high incidence and mortality with poor prognosis, creating an urgent need for novel prognostic models and therapeutic strategies. Protein palmitoylation, an important post-translational modification, exerts pivotal effects on tumorigenesis; however, its prognostic and mechanistic relevance in COAD remains unknown. This study determined palmitoylation-related prognostic biomarkers and probable therapeutic targets to treat COAD. We integrated transcriptomic datasets from the TCGA and identified prognostic genes related to palmitoylation by conducting differential expression analysis, weighted gene correlation network analysis, and Cox proportional hazards modeling using the least absolute shrinkage and selection operator (LASSO) method. Based on these genes, we established a robust risk signature and nomogram that consistently stratified COAD patients into distinct risk groups. Multi-omics profiling, including immune infiltration assessment, drug response prediction, and single-cell mapping, revealed distinct molecular and cellular programs within each risk group. In vitro and in vivo studies were conducted using the representative hub gene PHGDH to validate its function in COAD. A risk score model comprising three palmitoylation-related genes (PHGDH, LAMA2, and PBXIP1) stratified COAD patients into subgroups with distinct survival, immune infiltration, and drug sensitivity profiles. PHGDH was identified as the most dysregulated candidate. Functional studies revealed that depleting PHGDH significantly repressed cell proliferation and induced apoptosis. Critically, pharmacological inhibition of PHGDH palmitoylation markedly suppressed tumor growth in vitro and in xenograft models, indicating its feasibility as a therapeutic target for COAD. The palmitoylation-related risk model established in this study demonstrates strong prognostic predictive capability for COAD, offering a promising new clinical stratification tool. Furthermore, PHGDH was validated as a key functional target whose activity is regulated by palmitoylation, presenting a novel therapeutic opportunity for COAD treatment. The online version contains supplementary material available at 10.1007/s13402-026-01207-4.
Progression to castration-resistant prostate cancer (CRPC) is shaped by dynamic interactions within the tumor microenvironment (TME). However, the specific cellular crosstalk driving therapeutic resistance and metastasis remains incompletely defined. This study aims to identify key signaling axes between therapy-resistant luminal progenitor (luminal-2) cells and immune components in the TME, particularly tumor-associated macrophages (TAMs), and to determine how these interactions promote immunosuppression and cancer stem-like cell expansion during disease progression. We employed an integrative phenomics approach combining single-cell transcriptomics with genetically engineered mouse models (GEMMs) and orthotopic allograft models of prostate cancer. Spatiotemporal changes in cell populations were profiled across disease stages. The functional contribution of the CX3CL1-CX3CR1 axis was evaluated through genetic ablation of Cx3cr1 in host mice, followed by assessment of TAM infiltration, luminal progenitor cell dynamics, tumor growth, and immunosuppression signature score. Single-cell profiling revealed a distinct luminal-2 progenitor population with high CX3CL1 expression that recruits CX3CR1+ TAMs and supports a pro-tumoral program. These CX3CL1hi luminal-2 cells and CX3CR1hi TAMs expand in a stage-specific manner and co-evolve during CRPC progression, forming an immunosuppressive and pro-metastatic niche. Host Cx3cr1 deletion disrupted this signaling axis, leading to reduced TAM infiltration, suppression of luminal progenitor cells expansion, and significant inhibition of tumor growth and progression. The CX3CL1-CX3CR1 axis functions as a critical mediator of reciprocal signaling between luminal-2 progenitors and TAMs that promotes immune evasion, stemness maintenance, and therapeutic resistance in prostate cancer. Disrupting this pathway impairs the pro-tumoral niche and may represent a promising therapeutic approach for advanced prostate cancer.
Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with limited treatment options. Although radiotherapy remains a cornerstone of curative treatment, intrinsic and acquired radioresistance frequently lead to locoregional recurrence and disease progression. DDX39A, a DEAD-box RNA helicase, regulates RNA metabolism in diverse cellular contexts; however, its role in ESCC pathogenesis and therapeutic resistance remains unclear. Bioinformatics analyses, immunohistochemistry, and functional assays were performed to characterize the role of DDX39A in ESCC. Tandem mass tag-based proteomics was used to identify downstream effectors. Mechanistic studies included RIP-qPCR, ChIP-qPCR, and dual-luciferase reporter assays. The therapeutic relevance was further validated using murine xenograft models. DDX39A was significantly upregulated in ESCC tissues and cell lines, and its high expression correlating with increased tumor proliferation. DDX39A knockdown suppressed malignant phenotypes and markedly enhanced radiosensitivity. Mechanistically, SP1 was prioritized from proteomic screening owing to its central role as a transcription factor regulating DNA repair gene expression. DDX39A directly binds to SP1 mRNA, stabilizing it and enhancing its translation efficiency without affecting transcription. The resulting increase in SP1 protein promotes binding to the − 223/−214 bp region of the Ku70 promoter, thereby transcriptionally activating this key component of the non-homologous end joining pathway and contributing to radioresistance. Rescue experiments confirmed that the DDX39A–SP1–Ku70 axis is both necessary and sufficient to mediate radioresistance. In vivo, DDX39A silencing enhanced radiosensitivity and improved tumor control in ESCC models. These findings identify DDX39A as a promising therapeutic target in ESCC radioresistance. The DDX39A–SP1–Ku70 axis provides a mechanistic rationale for the development of novel radiosensitization strategies. The online version contains supplementary material available at 10.1007/s13402-026-01206-5.
Breast cancer continues to be a major contributor to cancer-associated deaths among the female population globally. This study aims to investigate the functional role, underlying mechanisms, and clinical relevance of Cell death-inducing DFFA-like effector C (CIDEC) in breast cancer pathogenesis. Integrated bioinformatics analysis of three gene expression datasets identified hub genes via protein-protein interaction network and multiple machine learning algorithms. The tumor-suppressive effects of CIDEC were evaluated in vitro using breast cancer cell lines by assessing viability, proliferation, migration, invasion, and apoptosis, and in vivo via a xenograft model. Mitochondrial function, autophagy, and the cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signaling pathway were assessed using a pathway agonist and an autophagy inhibitor. A marked reduction in CIDEC expression was observed in breast cancer tissues and cellular models. CIDEC effectively curtailed tumor progression by impeding proliferation, migration, and invasive capacity, coupled with the induction of apoptotic cell death. Mechanistically, CIDEC impaired mitochondrial fitness, characterized by reduced adenosine triphosphate (ATP) production, dissipated mitochondrial membrane potential, and elevated reactive oxygen species. Concurrently, CIDEC blocked protective autophagy. These effects were mediated through the suppression of the cGMP/PKG pathway. Activating this pathway with 8-Br-cGMP reversed the tumor-suppressive phenotypes and mitochondrial dysfunction induced by CIDEC, whereas inhibiting autophagy attenuated this rescue. Our findings demonstrate that CIDEC functions as a novel tumor suppressor in breast cancer by disrupting mitochondrial fitness and inhibiting protective autophagy via the cGMP/PKG pathway. The CIDEC-cGMP/PKG axis represents a promising therapeutic target for breast cancer intervention. Not applicable. The online version contains supplementary material available at 10.1007/s13402-026-01211-8.
Hepatocellular carcinoma (HCC), the most common primary liver cancer, typically arises in a context of chronic inflammation driven by metabolic dysfunction, long-term alcohol use, viral hepatitis, and other etiologies. This study aimed to investigate whether intrahepatic and circulating immune profiles in HCC patients correlate with patient characteristics or clinical parameters. Fresh tumor tissue, paired non-tumor liver tissue, and peripheral blood samples from 93 patients with HCC were analyzed using multiparametric flow cytometry to characterize lymphocyte subsets (T cells, NK cells, NKT cells, and B cells), immune checkpoint molecule expression (ICOS, 4-1BB, OX40, PD-1, TIM-3, LAG-3, and CTLA-4), and activation status. Associations between immune parameters and patient demographic or clinical features were assessed. Circulating alpha-fetoprotein (AFP) levels positively correlated with tumor-infiltrating PD-1high CD8+ T cell frequency (r=0.45, p<0.0001), but this correlation was not observed in non-tumoral or circulating compartments. AFP-producing HCC is linked to intra-tumoral immune exhaustion, marked by PD-1high CD8+ T cell accumulation, suggesting a localized immunosuppressive effect mediated by tumor-secreted AFP. The online version contains supplementary material available at 10.1007/s13402-026-01170-0.
Bladder cancer (BCa) represents the fourth most prevalent malignancy worldwide, characterized by unfavorable clinical outcomes. The functional significance and molecular mechanisms underlying circular RNAs in BCa pathogenesis require further investigation. This study reveals that circBARD1 suppresses histone lactylation-driven tumor progression by modulating ENO1 protein stability in bladder cancer. Functional characterization of circBARD1 was performed through gain-of-function experiments in T24 and TCCSUP cell lines. RNA immunoprecipitation (RIP) and immunoprecipitation assays were employed to investigate circBARD1-ENO1 interactions. CUT&Tag and chromatin immunoprecipitation (ChIP) assays were conducted to examine H3K18 lactylation-mediated transcriptional regulation of CCNA2. CircBARD1 expression was significantly downregulated in bladder cancer tissues. Ectopic expression of circBARD1 inhibited malignant proliferation and migration capacities in BCa cell lines. Furthermore, circBARD1 demonstrated negative regulation of glycolytic flux and intracellular lactate accumulation. Mechanistic studies revealed that circBARD1 physically interacts with ENO1 protein, facilitating its ubiquitination-mediated proteasomal degradation mediated by FBXW7. This circBARD1/ENO1 regulatory axis attenuates tumor progression through suppression of H3K18 lactylation and subsequent downregulation of CCNA2 transcription. Our findings establish that circBARD1 functions as a tumor suppressor in bladder cancer by promoting ENO1 ubiquitination and degradation, thereby inhibiting histone lactylation-mediated oncogenesis. This study provides new insights into therapeutic targets for clinical management of bladder cancer. The online version contains supplementary material available at 10.1007/s13402-026-01180-y. CircBARD1 promoted the degradation of ENO1 (a critical enzyme in glycolysis) by enhancing its ubiquitination mediated by FBXW7, which then plays a vital role in suppressing tumor growth driven by H3K18 lactylation-CCNA2 axis in human bladder cancer [Image: see text] The online version contains supplementary material available at 10.1007/s13402-026-01180-y.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, a status primarily attributable to its intricate molecular circuitry. The histone acylation network serves as a key orchestrator of PDAC progression through epigenetic reprogramming, making its regulatory components high-value targets for groundbreaking therapeutic interventions. Here, we review how diverse histone acylations govern pancreatic cancer biology. We first outline the established roles of acetylation in proliferation, metastasis, and immune evasion. Subsequently, we focus on novel modifications intimately linked to tumor metabolic reprogramming, with a particular emphasis on histone lactylation. We also explore emerging modifications such as succinylation and propionylation as potential therapeutic targets. We further underscore that these diverse acylations exhibit extensive crosstalk, forming an intricate and dynamic regulatory network mediated by shared enzymatic “writers” and “erasers” (e.g., p300, HDACs), and exerting synergistic or antagonistic effects on key genes including MYC and GATA binding protein 6 (GATA6). By providing a comprehensive deciphering of the dysregulated histone acylation network, this review highlights its significant transformative potential. Such understanding not only unveils novel pathogenic drivers of pancreatic tumorigenesis but also establishes a mechanistic foundation for precision oncology. Furthermore, we evaluate the current landscape of clinical trials and discuss the potential of epigenetic agents to sensitize tumors to conventional or targeted therapies. By bridging the gap between complex molecular crosstalk and clinical application, this review aims to provide a practical framework for the rational design of targeted inhibitors and the formulation of synergistic combination therapies to overcome current treatment limitations and therapeutic resistance. None. Not applicable.