Background: RNA-binding proteins (RBPs) and ferroptosis have been demonstrated to play important roles in the progression of chronic rhinosinusitis (CRS). However, the regulatory mechanisms underlying the interaction between RBPs and ferroptosis in CRS, particularly regarding mitochondrial metabolism, remain elusive.
Methods: Hub genes correlated with RBP-related genes, ferroptosis-related genes and mitochondrial-related genes were identified by integrated bioinformatics analysis. CRS in vivo models were constructed, clinical samples were collected, and mechanistic analyses were performed for validation.
Results: ZFP36L1 was identified as the hub gene associated with CRS development. In vivo experiments demonstrated that ZFP36L1 directly binds to the 3′-untranslated region of CAMK2A mRNA and promotes its degradation through AU-rich element recognition. ZFP36L1 knockout in CRS mouse models restored CAMK2A expression and significantly attenuated ferroptosis markers, reactive oxygen species accumulation and mitochondrial dysfunction. Rescue experiments revealed that CAMK2A knockdown reversed the protective effects of ZFP36L1 depletion on ferroptosis and mitochondrial quality control. Clinical samples confirmed that ZFP36L1 expression was inversely correlated with CAMK2A levels, and both were associated with disease severity.
Conclusion: This study identifies ZFP36L1–CAMK2A as a contributory regulatory mechanism in CRS pathogenesis. ZFP36L1 promotes ferroptosis by destabilizing CAMK2A mRNA, leading to mitochondrial dysfunction and subsequent epithelial cell death. These findings provide new mechanistic insights into CRS progression and identify potential therapeutic targets.
Highlights:
Recent studies have demonstrated the significance of gut microbiota in the colorectal cancer (CRC) pathogenesis. But their role in carcinogenesis remains to be established. Thus, we established a clinical cohort and the faecal samples from CRC and healthy control were collected. Our metagenomic analysis found that the presence of Parvimonas micra exhibited the most significant relationship with the occurrence of CRC. Increased colonisation of P. micra in CRC was validated with analysis of 1379 faecal metagenomes from eight public cohorts. Untargeted metabolomics subsequently identified an accumulation of phenyllactic acid (PLA) in faecal samples from CRC patients. Higher concentration of PLA was detected in the supernatant from our isolated P. micra. Whole-genome sequencing confirmed that a series of genes associated with PLA biosynthesis such as pdhD were observed in the P. micra genome. Importantly, both P. micra and PLA-induced carcinogenesis in ApcMin/+ and azoxymethane/dextran sulphate sodium salt mice model. The roles of P. micra and PLA in CRC development were associated with DNA damage. Engineered Escherichia coli BL21 that encoded the heterologous pdhD from P. micra could also induce DNA damage. Mechanically, PLA-induced DNA damage and CRC carcinogenesis were significantly alleviated in Ahr−/− mice. Aryl hydrocarbon receptor (AHR) inhibitor exhibited a therapeutic potential to reduce mice carcinogenesis. These findings established the role of P. micra and its metabolite, therefore providing diagnostic and therapeutic targets for treating CRC.
Objective: Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy, whereas its molecular and cellular mechanisms remain poorly understood. This study aimed to characterize the cellular heterogeneity of FCD and investigate the function of ferroptosis in FCD pathogenesis.
Methods: Single-nucleus RNA sequencing was carried out on epileptogenic cortical tissues from 18 patients with FCD and 6 perilesional control samples with normal histology. Data were analysed using uniform manifold approximation and projection for dimensionality reduction and visualization. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. UCell scoring and gene set enrichment analysis (GSEA) were applied to assess pathway activity. Expression levels of ferroptosis-related genes (FRGs) were validated by immunofluorescence, and biochemical assays quantified the levels of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and lipid peroxides (LPO).
Results: A total of 170 747 nuclei were profiled, resolving five major cell types, including inhibitory neurons, excitatory neurons, astrocytes, microglia and oligodendrocytes. DEGs across these populations were significantly enriched in ferroptosis and oxidative stress–associated pathways. UCell and GSEA highlighted remarkable alterations in ferroptosis, apoptosis and oxidative stress, particularly in inhibitory neurons and astrocytes. Immunofluorescence confirmed upregulation of key FRGs, including ferritin light chain, ferritin heavy chain 1, poly rC binding protein 1, microtubule-associated protein 1 light chain 3B and prion protein-encoding gene, in FCD tissues. Concordantly, biochemical assays demonstrated reduced SOD and GSH levels, alongside elevated MDA and LPO levels, confirming the transcriptional and histological findings.
Conclusions: The results indicated that ferroptosis may play a notable role or act as a concurrent mechanism in the pathogenesis of FCD, potentially contributing to the neuronal and glial dysfunction and epileptogenesis. Integrating transcriptomic, histological and biochemical data, this study demonstrated that targeting ferroptosis-related pathways may hold promise as a potential therapeutic strategy for FCD, providing new insights into the molecular mechanisms underlying this condition.
Highlights:
Background: Retroperitoneal sarcoma (RPS) is a type of malignant tumour arising from mesenchymal tissues within the retroperitoneal space. RPSs tend to develop covertly and are often undiscovered when they have already grown significantly and invaded surrounding tissues and organs. These malignancies demonstrate high recurrence rates, present surgical challenges and exhibit limited responsiveness to radiotherapy and chemotherapy. Serum-derived molecules are known to play critical roles in tumourigenesis and tumour progression. However, the serum molecular profile of RPS patients remains unclear.
Methods: We performed multi-omics analysis of serum samples from patients with retroperitoneal dedifferentiated liposarcoma. Prolactin concentrations were quantified using Enzyme-Linked Immunosorbent Assay (ELISA). RNA-seq facilitated the identification of candidate signalling pathways, while gene expression was validated through quantitative polymerase chain reaction, immunohistochemistry and western blot analyses. Molecular mechanisms underlying transcriptional regulation were investigated through Chromatin Immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase reporter gene assays.
Results: Integrative multi-omics profiling identified significant perturbations in galactose metabolism coupled with marked elevation of prolactin (PRL) levels in Retroperitoneal Liposarcoma (RLPS) patients. Further screening of serum prolactin levels in 100 patients with retroperitoneal tumours revealed that 90% of the cases exhibited hyperprolactinaemia in our research cohort, encompassing both malignant sarcomas and benign tumours. Studies at the clinical sample, cellular and animal levels have found that abnormally elevated prolactin in the serum can originate from sarcoma tissues. Mechanistic investigations identified SRY-box transcription factor 4 (SOX4) as a previously unrecognised transcriptional regulator of PRL. Functionally, PRL not only enhanced liposarcoma cell and fibrosarcoma cell proliferation but also conferred resistance to MDM2 inhibitors. Signalling pathway analysis revealed that PRL activates the Janus Kinase–Signal Transducer and Activator of Transcription Pathway (JAK–STAT) signalling pathway and up-regulates c-MYC expression.
Conclusions: This study indicates that PRL can serve as an oncogenic driver and therapeutic target. The identification of SOX4–PRL–c-MYC signalling axis provides actionable insights for developing novel therapeutic strategies against this malignancy.
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Background: Focal cortical dysplasia (FCD) is a common neurodevelopmental disorder characterised by cortical malformations and is a major cause of drug-resistant epilepsy. FCD type I (FCDI) presents with architectural abnormalities of the neocortex but without cytological abnormalities. Currently, FCDI remains a significant clinical challenge.
Methods: Epileptogenic cortical tissues from three FCDI patients and three relatively normal neocortical tissues as controls were analysed using single-nucleus RNA sequencing and spatial transcriptomic for multi-omics integration.
Results: This study constructed a single-cell spatial transcriptomic atlas of the epileptogenic cortex from FCDI patients. Excitatory neurons (ENs) and astrocytes (Ast) exhibited the most prominent alterations in FCDI. Hub genes associated with FCDI were identified in ENs, and a transcription factor (TF)‒hub gene regulatory network was constructed. Notably, CBLN2highEx-1 was identified as being potentially involved in processes related to neuronal hyperexcitability and cortical development in FCDI. Western blot and immunofluorescence assays validated the altered expression of selected key genes and TFs at the protein level. Additionally, Ast exhibited increased heterogeneity, impaired differentiation and a higher proportion of immature Ast in FCDI, with predicted TFs regulating this process. Further analysis revealed aberrant signalling pathways and ligand‒receptor interactions between ENs and Ast in FCDI, with spatial co-localisation patterns that may contribute to disease progression.
Conclusions: This study highlights the specific dysregulation of ENs and Ast, along with aberrant cellular communication, which may play a critical role in the pathogenesis of FCDI. These findings provide novel insights into the molecular mechanisms underlying FCDI and offer potential therapeutic targets for precision treatment and drug development.
Background: Metabolic dysfunction–associated steatotic liver disease (MASLD) and advanced fibrotic stages are significant contributors to cirrhosis and liver-related mortality, yet no therapies directly target fibrosis in the later stages of the disease. Fibroblast growth factor 10 (FGF10) facilitates epithelial repair, yet its function and epithelial receptor requirements in chronic liver fibrogenesis are unclear.
Methods: We quantified hepatic FGF10 and fibroblast growth factor receptor 2 (FGFR2) expression across fibrosis stages in biopsies from patients with MASLD and mouse models. We then augmented hepatic FGF10 using adeno-associated virus-mediated liver expression or subcutaneous recombinant human FGF10 in carbon tetrachloride (CCl4) and high-fat diet plus CCl4-induced advanced fibrosis. Histology, immunohistochemistry, biochemistry, RNA sequencing and primary hepatocytes and hepatic stellate cells (HSCs) assays were used to assess the therapeutic effects and underlying mechanisms.
Results: Hepatic FGF10 and FGFR2 protein expression were significantly reduced at advanced disease stages. Restoring FGF10 led to regression-associated remodelling of established bridging fibrosis, a decrease in inflammatory cytokines and a reduction in hepatocyte apoptosis, even with continued CCl4 exposure, indicating histologic regression rather than slowed progression. These therapeutic effects required hepatocyte FGFR2, as hepatocyte-specific FGFR2 deletion abolished protection and the associated transcriptional reprogramming of matrix and cytokine networks. In primary hepatocytes, FGF10 activated FGFR2–FGFR substrate 2α (FRS2α) signalling, increased inhibitory phosphorylation of glycogen synthase kinase 3β at Ser9 and suppressed nuclear factor kappa B, thereby lowering transforming growth factor β1 and other cytokines and indirectly limiting HSC activation. The efficacy extended to a high-fat diet plus CCl4 model of steatohepatitis.
Conclusions: These findings elucidate a hepatocyte-centric FGF10–FGFR2 axis functioning as an epithelial regulator of inflammation and fibrogenesis. Hepatocyte-targeted reinforcement of FGFR2 signalling, alone or combined with metabolic therapies, represents a translational strategy to reprogram the fibrotic niche and facilitate fibrosis regression-associated architectural remodelling in advanced liver fibrosis.
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Background: Exportin-1 (XPO1), a key regulator of nucleocytoplasmic transport, is frequently dysregulated in acute myeloid leukemia (AML) and contributes to leukemogenesis, disease progression and therapeutic resistance. Selective inhibitors of nuclear export (SINEs), especially selinexor and eltanexor, have shown promising antileukemic potential. However, their clinical value, optimal therapeutic positioning and rational use in AML remain to be fully clarified.
Methods: We collected and reviewed relevant literature to summarize the biological roles of XPO1 in AML and the therapeutic potential of XPO1 inhibitors in preclinical and clinical settings.
Results: In this review, we focus on the nuclear export function of XPO1 and its pathogenic role in AML. We summarize the mechanisms of action, preclinical evidence, clinical trial results, adverse effects, resistance mechanisms and potential response biomarkers associated with XPO1 inhibitors in AML.
Conclusions: XPO1 inhibition has emerged as a promising therapeutic strategy for AML, offering a novel approach to targeting aberrant nucleocytoplasmic transport and overcoming treatment resistance. Future studies should focus on optimizing dosing schedules, identifying predictive biomarkers and developing effective combination strategies in molecularly selected AML populations.
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Background: Hepatic ischaemia/reperfusion (I/R) injury poses a common clinical dilemma encountered during liver transplantation (LT), characterised by substantial cellular death and inflammation reactions. Ubc9, the sole E2 conjugating enzyme of SUMOylation, has long been recognised to regulate diverse biological and pathological processes. However, its impact on I/R-induced liver damage is yet to be elucidated.
Methods: The expression levels of UBC9 in patients undergoing LT were analysed. Hepatocyte-specific Ubc9-deficient or transgenic mice were utilised in an in vivo model of hepatic I/R, alongside in vitro experiments that employed hypoxia/reoxygenation stimulation. The investigation focused on Ubc9's role in liver damage due to I/R and the underlying mechanisms through a range of phenotypic analyses and biological techniques.
Results: Herein, we found that hepatic tissues from patients with LT are featured by a significant downregulation of UBC9 expression. Studies in 68 donor hepatic biopsies further demonstrated a negative correlation between UBC9 expression and liver injury in patients with LT. Similarly, murine liver I/R was coupled with an obvious decrease in Ubc9 expression. Hepatocyte deficient in Ubc9 exacerbated liver injury in liver I/R, while Ubc9-overexpression showed the opposite phenotype. Mechanistically, Ubc9-mediated SUMOylation of Ninj1 at lysine K103 inhibited its membrane localisation and damage-associated molecular patterns (DAMPs) release in hepatocytes, subsequently inhibited nuclear factor-kappa B (NF-κB) signalling in macrophages and curtailing inflammatory cytokines production.
Conclusions: These findings further suggest that Ubc9-mediated SUMOylation of Ninj1 at lysine K103 may represent a potential therapeutic strategy for safeguarding the liver against I/R injury in clinical settings.
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Background: Cancer-associated fibroblasts (CAFs) within the tumour microenvironment play a pivotal role in colorectal cancer (CRC) progression and therapeutic resistance. Serine/threonine protein kinase 25 (STK25) exerts multiple roles in tumourigenesis; however, its role in mediating tumour–stroma crosstalk remains largely unexplored.
Methods: Primary CAFs were isolated from CRC patient tissues and characterised to confirm their identity. The effects of STK25 expression on CAF activity and CAF-mediated tumour progression were evaluated both in vitro and in vivo. Western blot, qRT-PCR, ChIP and dual-luciferase reporter assays were performed to elucidate the mechanism by which STK25 regulated CAF activation. Moreover, the effect of STK25 expression on CAF-induced cetuximab resistance was assessed in vitro and in vivo. The clinical significance of STK25 expression was determined in CRC patient tissues, tissue microarrays and patient-derived organoids.
Results: Knockdown of STK25 in CRC cells enhanced CAF proliferation, migration and activation, whereas its overexpression exhibited the opposite effect. STK25-knockdown-mediated CAF activation subsequently promoted CRC cell proliferation and metastasis. Moreover, STK25 depletion combined with CAFs significantly enhanced CRC tumour growth in vivo. Mechanistically, STK25 deficiency activated the NF-κB pathway, leading to p50 phosphorylation which directly bound to the AREG promoter, thereby transcriptionally up-regulating AREG expression. In addition, STK25-regulated AREG/EGFR axis mediated the crosstalk between CRC cells and CAFs. More importantly, CAFs conferred resistance to the anti-EGFR antibody cetuximab, which could be reversed either by STK25 overexpression or by AREG-neutralising antibody treatment. Clinically, low STK25 expression correlated with elevated CAFs marker levels and poor cetuximab response in CRC patients.
Conclusions: Our findings identified STK25 as a critical regulator of the NF-κB/AREG/EGFR axis in tumour–CAF communication and highlight its potential as a therapeutic target for overcoming CAF-induced cetuximab resistance in CRC.
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Purpose: Perioperative treatment of gastric and gastroesophageal junction (G/GEJ) cancer is evolving towards multimodal strategies incorporating HER2-targeted therapy, immunotherapy and chemotherapy. Disitamab vedotin (RC48), an HER2-targeted antibody–drug conjugate, shows promising antitumour activity and potential synergy with immune checkpoint inhibitors. This study evaluated neoadjuvant RC48 combined with camrelizumab and S-1 in resectable HER2-overexpressing locally advanced G/GEJ adenocarcinoma.
Methods: Patients with histologically confirmed HER2-overexpressing (IHC 3+ or 2+) resectable G/GEJ cancer staged as cT3-4aN1-3M0 were enrolled in this prospective single-arm phase II study. Patients received three 3-weekly cycles of RC48, camrelizumab and S-1 before surgery. Pathological complete response (pCR) was defined as the primary endpoint, whereas major pathological response (MPR), objective response rate (ORR), tumour downstaging, disease-free survival (DFS), overall survival (OS) and safety were evaluated as secondary endpoints. Exploratory circulating tumour DNA (ctDNA) methylation profiling (PredicineEPIC) assessed molecular response dynamics and ERBB2 copy number variation.
Results: From 18 September 2022 to 12 December 2024, 32 patients were enrolled; 24 proceeded to D2 resection. The ORR after neoadjuvant therapy was 80.0% (24/30). In the surgical cohort, pCR and MPR were achieved in 25.0% (6/24) and 45.8% (11/24) of patients, respectively, with an R0 resection rate of 100%. The median DFS and OS were not reached at the time of analysis. In the ctDNA substudy (n = 14), methylation-derived tumour fraction declined during therapy and ERBB2 plasma copy number gain aligned with tissue HER2 status. Treatment-related adverse events of grade ≥3 were reported in 31.3% of patients.
Conclusion: Neoadjuvant RC48 combined with camrelizumab and S-1 showed potential antitumour activity with an acceptable safety profile in HER2-overexpressing locally advanced resectable G/GEJ adenocarcinoma.
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Background: Triple-negative breast cancer (TNBC) remains a major clinical challenge because of its aggressive characteristics, limited targeted treatment options, and frequent chemoresistance. However, the molecular mechanisms governing protein stability that drive TNBC progression and therapeutic resistance remain incompletely understood.
Methods: TMEM92 expression and clinical relevance were evaluated using public datasets, patient specimens, and TNBC cell models. Loss-of-function, rescue, xenograft, protein interaction, and ubiquitination assays were performed to determine the biological function and molecular mechanism of TMEM92 in TNBC progression and cisplatin response.
Results: TMEM92 was prominently expressed in TNBC and correlated with poor prognosis. Functionally, depletion of TMEM92 suppressed TNBC cell proliferation, migration, invasion, and survival while promoting apoptosis in vitro and in vivo. Mechanistically, TMEM92 directly associated with DEAD-box helicase 3 X-linked (DDX3X) and protected it from degradation by the E3 ubiquitin ligase tetratricopeptide repeat domain 3 (TTC3). TMEM92 competitively prevented TTC3 binding to DDX3X, thereby inhibiting TTC3-mediated K48-linked ubiquitination and subsequent proteasomal degradation of DDX3X. Re-expression of DDX3X rescued the anti-tumor effects induced by TMEM92 knockdown. Therapeutically, TMEM92 targeting sensitized TNBC cells and xenograft tumors to cisplatin. TMEM92 knockout reduced the cisplatin IC50 by 44.0% in MDA-MB-231 cells and 42.9% in BT-549 cells, and TMEM92 depletion enhanced cisplatin-induced tumor growth inhibition by approximately 70.6% compared with cisplatin alone.
Conclusions: This study identifies a novel TMEM92DDX3XTTC3 axis that regulates DDX3X protein stability and drives TNBC progression and chemoresistance, revealing a potential prognostic and therapeutic vulnerability in TNBC.
Background: Traumatic spinal cord injury (SCI) induces a robust local inflammatory response that can both facilitate repair and exacerbate pathology. Hydroxycarboxylic acid receptor 2 (Hcar2) is known to exert immunomodulatory effects; however, its role in SCI and its potential for targeting Hcar2 to alleviate motor deficits remain unclear.
Methods: The spinal cord transcriptome following SCI, with a focus on Hcar2, was analysed via publicly available single-cell RNA sequencing datasets from mice and rhesus macaques. Additionally, an in vivo SCI mouse model with Hcar2 knockout and an in vitro LPS-induced BV2 microglial model were established to assess Hcar2 gene and protein expression, microglial activation and inflammatory responses via bulk RNA sequencing, immunofluorescence staining, Western blotting, and real-time polymerase chain reaction. To evaluate the protective effects of Hcar2 activation, niacin, a known Hcar2 agonist, was administered to mice or BV2 cells, followed by assessments of the inflammatory response and motor function.
Results: Hcar2 gene expression, which was enriched predominantly in spinal cord microglia, was upregulated following SCl, peaking at 7 days post-SCl. Genetic knockout of Hcar2 decreased the percentage of impaired anti-inflammatory polarized microglia and increased the inflammatory response. In contrast, Hcar2 activation with niacin in LPS-stimulated microglia BV cell models reversed mitochondrial dysfunction, increased the oxygen consumption rate and reduced the expression of the cytokines IL-6 and IL-1β. The administration of niacin to SCl mice upregulated anti-inflammatory microglia, reduced the expression of multiple proinflammatory cytokines, increased the number of motor neurons and improved motor function recovery. Notably, all these protective effects were abolished by genetic loss of Hcar2.
Conclusions: Hcar2 serves as a critical regulator of microglial polarization, promoting the switch from a proinflammatory phenotype to an anti-inflammatory phenotype through immunometabolic reprogramming. Targeting Hcar2 with niacin may offer a translatable therapeutic strategy to improve functional recovery after SCl.
Key Points:
Combination therapies are critical for enhancing and prolonging the efficacy of EGFR inhibitors. Here, we uncover FUNDC1-dependent mitophagy as a key protective mechanism in EGFR-mutant non-small cell lung cancer (NSCLC). We discover that nitidine, a bioactive component of the traditional Xihuang Pill formulation, synergises with the EGFR inhibitor osimertinib. Mechanistically, nitidine and osimertinib synergistically disrupt FUNDC1-mediated mitophagy, leading to mitochondrial dysfunction and accumulation of reactive oxygen species in EGFR-mutant NSCLC. We further show that both osimertinib and nitidine decrease HIF-1α protein levels, thereby downregulating FUNDC1 expression. Nitidine-induced downregulation of HIF-1α and FUNDC1 depends on the mitochondrial transporter ABCB6. Notably, acquired resistance to osimertinib exhibits adaptive downregulation of FUNDC1, rendering resistant EGFR-mutant NSCLC cells more sensitive to nitidine. Collectively, these findings position nitidine as a promising therapeutic strategy to enhance the efficacy of EGFR inhibitors and overcome osimertinib resistance in EGFR-mutant NSCLC.
Background and aims: Existing imaging and serum-marker assays miss many early liver cancers, especially in high-risk chronic liver disease carriers. We aimed to create a highly accurate, non-invasive, methylation-based liquid biopsy for early detection.
Methods: We used a comprehensive, multi-platform, multi-cohort strategy for marker discovery, starting with methylation profiling of hepatocellular carcinoma samples from TCGA and in-house cohorts. From 30 initial candidates, nine highly liver-specific methylation markers were shortlisted, and three optimal cfDNA markers (RNF135, CHFR, PAX5) were selected to develop a robust diagnostic model, tuned in a training set (N = 280) and locked in an internal testing set (N = 124). The model was then validated in a prospective, large-scale trial conducted at four geographically distinct Chinese centres.
Results: The clinical trial included 1097 participants from two groups, (i) a diagnosing group (N = 646) that prospectively enrolled individuals without prior diagnostic results and represented a real-world high-risk population, and (ii) a diagnosed group recruited after pathology confirmation. Overall, the model achieved 94.43% (95% confidence interval, 92.12–96.09%) sensitivity and 95.16% (92.78–96.78%) specificity for liver cancer, with stage-I sensitivity of 93.10% (89.78–95.40%). Within the diagnosing group, overall sensitivity was 93.99% (91.28–95.90%), and for the 267 stage-I cases, it reached 92.88% (89.15–95.39%). As for specificity, it remained high across confounders: 92.78% (85.84–96.46%) in cirrhosis, 91.74% (85.46–95.45%) in other-cancer interference samples. Besides, the model outperformed the traditional liver cancer biomarker AFP and showed changes in methylation signals before and after surgery, suggesting a possible role in perioperative monitoring. Each centre independently reported sensitivities and specificities exceeding 90%, demonstrating robust geographic performance.
Conclusions: Using a systematic marker-discovery pipeline and a multi-centre prospective cohort, we developed a methylation-based liquid biopsy that reliably detects early liver cancer in high-risk populations.
Clinical trial number: Chictr.org identifier: ChiCTR2400092883.
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First published in Clinical and Translational Medicine. 2021;11:e495. https://doi.org/10.1002/ctm2.495
Upon recent review of figures in this paper, we found the image mislabelling error that occurred while organizing data, which resulted in the similarity between the western blot panels in Figure 3J (right) and Figure 6A. In addition, an H&E image from the shHAT1 group was inadvertently mislabelled as shHAT1+ENZ in Figure 5H during file archiving.
After carefully re-examining all original data, we confirmed that the two errors were due to the image mislabelling, and they do not affect the results and scientific conclusions of our study. However, to ensure the accuracy of the published record, we formally request the publication of the errata to correct the two figures. We sincerely apologize for this oversight and for any confusion it may have caused.
The corrected version of Figure 5H and Figure 6A is provided below.
Background: The standard treatment for locally advanced borderline-resectable esophageal squamous cell carcinoma (BR-ESCC) is still debated owing to insufficient evidence from clinical trials. An increasing number of clinical studies focus on investigating the use of immunotherapy in the treatment of oesophageal cancer. This phase II trial (NEOCRTEC-2001) aimed to assess the safety and efficacy of sintilimab in combination with cisplatin and nab-paclitaxel induction immunochemotherapy followed by surgery for BR-ESCC.
Methods: The NEOCRTEC2001 trial was a single-centre, open-label, nonrandomized, phase II study. Patients diagnosed with BR-ESCC were enrolled in the study and initially received 2–4 courses of induction immunochemotherapy at first. The subsequent treatment, surgery or definitive chemoradiotherapy, was determined based on reassessment by MDT. The primary endpoint of the study was the R0 resection rate.
Results: From September 2020 to June 2024, a total of 50 eligible patients diagnosed with BR-ESCC were enrolled. All eligible patients underwent induction immunochemotherapy as the initial treatment. After induction immunochemotherapy, 35 of 50 patients (70.0%) were considered resectable, and 29 patients (58.0%) underwent surgery. R0 resection was achieved in 28 patients (56.0%, 95% CI, 41.4–69.1%), and 9 patients (18.0%) achieved pathological complete response. The median follow-up time of all patients was 29.43 months. Patients in the R0 resection group demonstrated significantly superior overall survival (OS) and progression-free survival (PFS) compared to those in the non-R0 group (OS: not reached vs. 19.84 months; HR .25; 95%CI .08–.79, p = .001; PFS: not reached vs. 19.82 months; HR .30; 95%CI .10–.90, p = .006).
Conclusions: The regimen under investigation did not exhibit the anticipated statistical benefit in enhancing surgical conversion rates for BR-ESCC. Nevertheless, the treatment strategy of induction immunochemotherapy followed by surgery resulted in significant tumour downstaging and a significant pathological complete response rate. Patients who achieved R0 resection exhibited improved survival outcomes.
Trial registration: The study was registered at ClinicalTrials.gov (NCT04548440)
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Disorders of glucose metabolism, particularly type 2 diabetes and obesity, remain major therapeutic challenges because they involve dysfunction across multiple tissues, including pancreatic β-cells, peripheral insulin-sensitive tissues, and immune cells. ADP-ribosylation factor 6 (ARF6) is a regulator of membrane trafficking and cytoskeletal dynamics and may represent a mechanistically relevant link across these compartments. In this review, we summarise evidence suggesting that ARF6 may contribute to sustained second-phase insulin secretion, glucose transporter type 4 trafficking and recycling, and metabolic inflammation through effects on receptor and membrane trafficking. We also discuss pharmacological and nucleic acid-based approaches targeting ARF6 or its regulatory network. Current evidence suggests that direct systemic inhibition may be difficult to translate because of off-target risks, including possible disruption of endothelial barrier integrity. In addition, because cellular uptake of some delivery systems depends on endocytic pathways associated with ARF6, broad inhibition may also interfere with drug entry. Given these limitations, tissue-targeted and microenvironment-responsive nanodelivery systems may provide a more feasible strategy for modulating the ARF6 axis with greater spatial and temporal control. Overall, this review presents ARF6 as a potentially important mechanistic and translational entry point within the broader network that regulates glucose homeostasis, rather than as a single master regulator.
Background: Quantum biology explores how quantum mechanical phenomena—including coherence, tunneling, superposition, and spin dynamics—contribute to biological function. Although once considered negligible in warm and noisy biological environments, increasing evidence suggests that quantum effects play important roles in diverse living systems.
Objective: This review aims to summarize the current understanding of quantum biological mechanisms, highlight their relevance to physiology and disease, and discuss emerging biomedical and technological applications.
Methods: We reviewed recent experimental, computational, and theoretical advances in quantum biology, including studies employing ultrafast spectroscopy, quantum sensing, cryo-electron microscopy, and quantum simulation approaches. Key biological systems examined include photosynthetic complexes, enzymatic reactions, DNA base pairing, sensory systems, and mitochondrial electron transport.
Results: Accumulating evidence indicates that quantum coherence, tunneling, and spin-dependent processes contribute to photosynthetic energy transfer, enzymatic catalysis, proton transfer in DNA, magnetoreception, olfaction, and mitochondrial bioenergetics. Advances in quantum sensing and computational modeling have further enabled direct investigation of coherence dynamics and electron transfer mechanisms in biological systems. These findings suggest that quantum effects may influence aging, cancer, neurodegeneration, and metabolic dysfunction through mechanisms involving reactive oxygen species production, mutagenesis, and altered redox signaling.
Conclusion: Quantum biology is evolving from a speculative concept into an experimentally accessible and translationally relevant discipline. Integrating quantum principles with systems biology, multi-omics, and precision medicine may provide new opportunities for diagnostics, biomarker discovery, and therapeutic development. Continued advances in spectroscopy, quantum sensing, and quantum computing are expected to further establish the role of quantum phenomena in health and disease.
Background: Immune cells play a pivotal role in the pathogenesis of severe pneumonia. However, the global atlas of immune cells under this condition is not fully understood.
Methods: We conducted single-cell analyses of 275 411 cells isolated from matched lung tissue, bronchoalveolar lavage fluid, and peripheral blood from 12 patients with severe pneumonia and 5 donors, in order to identify the cross-compartment sharing pattern of activated immune cells and the roles they play in severe pneumonia.
Results: Our observations revealed that activated immune cells distributed across lung interstitia and airways (alveoli; Pattern 1a), including activated tissue-resident memory-like CD8+ T cells (T8_rms), plasma cells and plasmablasts, and the pro-inflammatory macrophages. The activated T8_rms were derived from circulating CX3CR1+ CD8+ T cells, which upregulated ITGAE and CXCR3 during lung infiltration. Similarly, plasma cells and plasmablasts expressing ITGAE and CXCR3 also indicated the potential lung interstitial-to-airway/alveolar sharing pattern. The pro-inflammatory macrophages interacted with T8_rms and plasma cells via the CXCL10-CXCR3 axis.
Conclusions: The lung interstitial-to-airway/alveolar cross-compartment sharing pattern of activated immune cells (Pattern 1a) provide a robust working hypothesis for clinical and translational research for severe pneumonia.
Background: Type 1 diabetes (T1D) is a lifelong autoimmune disease characterised by progressive immune-mediated destruction of insulin-producing beta (β)T1D-cells, leading to permanent insulin dependence and increased risk of microvascular and macrovascular complications. Despite advances in autoantibody screening and immunotherapies, major clinical challenges persist in early detection, accurate disease staging, prediction of progression and monitoring of therapeutic response. Current biomarkers provide limited insight into real-time β-cell stress and immune activity, restricting opportunities for timely and personalised intervention.
Rationale: Extracellular vesicles (EVs) are nano-sized membrane-bound particles released by virtually all cell types and carry proteins, lipids and nucleic acids reflective of their cellular origin and physiological state. Advances in EV isolation, multi-omics profiling and bioinformatics now enable detailed characterisation of EV cargo from accessible biofluids such as blood and urine. These developments position EVs as a minimally invasive platform to interrogate β-cell health, immune activation and systemic complications in T1D, while also offering a novel class of cell-free immunomodulatory therapeutics.
Content: This review synthesises current evidence on the role of EVs in T1D pathogenesis and clinical translation. We discuss how β-cell- and immune cell-derived EVs participate in antigen presentation, immune activation and inflammatory amplification, and how EV cargo signatures (proteins, miRNAs and other RNAs) reflect disease stage, progression and heterogeneity. We summarise emerging data on maternal, neonatal and urinary EVs as early-life and complication-associated biomarkers, and critically evaluate ongoing EV-based clinical studies in T1D. Finally, we examine the therapeutic potential of stem cell-derived and engineered EVs to modulate autoimmunity and preserve residual β-cell function.
Conclusion: EVs introduce a potentially clinically actionable layer of information linking cellular stress, immune dysregulation and tissue damage to measurable biomarkers and therapeutic opportunities in T1D. However, the majority of EV applications currently remain at the preclinical or early pilot‑study stage, with limited validation in large, longitudinal patient cohorts. Key challenges include biological heterogeneity, assay reproducibility and the need for standardised isolation, characterisation and regulatory frameworks. While rapid advances in EV technologies and early proof‑of‑concept clinical studies support their long‑term potential, substantial work is required before routine clinical implementation is feasible. For feasible clinical translation of EV-based applications, alignment with regulatory frameworks must be considered early to ensure analytical validity, standardisation and compliance with clinical and diagnostic approval pathways, as well as to address safety, efficacy and manufacturing requirements for EV-based therapeutics.
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Cancer progression is driven by coordinated alterations in signalling networks that regulate proliferation, plasticity, metabolism and therapeutic response. Although genetic and epigenetic mechanisms are well characterised, there is an increasing body of evidence that suggests bioelectric signalling constitutes an additional integrative regulatory layer in tumour biology. In diverse experimental systems, malignant cells consistently exhibit depolarised transmembrane potentials (Vm), which correlate with proliferation, stemness, invasion and therapy resistance, suggesting depolarisation as a conserved bioelectric hallmark of malignancy. This shifts the central question from whether cancer can be considered a bioelectric disease to the extent to which bioelectric signalling constitutes a relevant organising dimension of tumour biology.
However, a quantitative, translationally actionable framework for membrane potential in cancer is lacking. Existing studies and reviews have largely focused on individual ion channels, specific tumour contexts, or conceptual aspects of bioelectricity without systematically establishing Vm as a cross-tumour, systems-level state variable.
Here, we summarise approximately 15 years of experimental and translational research to evaluate the extent to which Vm functions as an integrative regulatory dimension of malignancy. Here, we define a state variable as a measurable, dynamically tuneable parameter that integrates multiple regulatory inputs and predicts system-level cellular behaviour.
At the same time, we identify key limitations in the current evidence base, including limited quantitative comparability across tumour types, incomplete mechanistic integration across regulatory layers, insufficient resolution of tumour heterogeneity and a lack of standardisation for clinical translation.
Based on this review, we introduce a quantitative framework and a structured translational roadmap for incorporating bioelectric state control into precision oncology. This establishes membrane potential as not only a supplementary biomarker, but also a functional pharmacodynamic indicator and an actionable control variable for state-guided therapeutic intervention.
Background: Cancer represents a major global public health issue, and recent research has focused on improving the efficacy of existing therapeutic approaches. In this context, oncolytic viruses have emerged as promising treatment options for advanced and treatment-resistant malignancies. Among them, adenoviruses are the most extensively studied due to their favourable safety profile, biological versatility and ease of genetic modification to enhance therapeutic performance.
Main body: Combination-based strategies integrating virotherapy with chemotherapy, radiotherapy or immunotherapy have been widely investigated to further improve anti-tumour efficacy. These approaches act through complementary and synergistic mechanisms, where chemotherapy can promote viral replication and increase tumour cell susceptibility through deoxyribonucleic acid (DNA) damage and transient immunomodulation, while radiotherapy enhances immunogenic tumour cell death by inducing sustained DNA damage. In parallel, immunotherapy—particularly immune checkpoint inhibition—can strengthen anti-tumour immunity by reversing T-cell exhaustion and increasing CD8+ T-cell infiltration and effector function. Collectively, these interactions amplify both direct viral oncolysis and immune-mediated tumour clearance. Additionally, clinical trial data suggest that intravenous administration of oncolytic adenoviruses may provide greater systemic antit-umour activity compared with intratumoural delivery, albeit with increased toxicity relative to localised injection.
Conclusion: Oncolytic adenoviruses have emerged as promising treatment options for advanced and treatment-resistant malignancies, particularly when integrated with chemotherapy, radiotherapy or immunotherapy. However, most studies included are early-phase trials conducted in small patient cohorts, underscoring the need for further research to better define safety profiles, long-term adverse effects, and the underlying mechanisms driving therapeutic response.
Background: The unpredictability of orthodontic tooth movement (OTM) and risks of root resorption stem from poorly understood mechanisms governing alveolar bone remodelling. Specifically, how macrophages transduce mechanical forces into osteoclastogenic signals remains elusive.
Methods: Our integrated approach combined analyses at multiple levels: clinical analysis of human periodontal ligament (PDL) tissues via qPCR and immunofluorescence; in vivo functional assessment using murine OTM and fracture models with macrophage-specific knockouts (for Piezo1 and Z-DNA binding protein 1 (Zbp1), designated as Piezo1cko and Zbp1cko); and in vitro mechanistic investigation through RNA sequencing of murine bone marrow-derived macrophages (BMDMs) and pharmacological screening. This multi-faceted strategy was employed to dissect the pathway.
Results: Mechanical stress activated macrophage Piezo1, triggering Ca2+ influx and subsequent upregulation of ZBP1. This axis was essential for pro-inflammatory cytokine release and osteoclastogenesis. Macrophage-specific deletion of Piezo1 or Zbp1 significantly decelerated OTM and preserved alveolar bone mass. Notably, Zbp1 overexpression rescued the remodelling defects in Piezo1-deficient mice. Virtual screening identified JNJ-10311795 as a ZBP1 modulator; its administration effectively slowed OTM and, conversely, accelerated fracture healing by shifting the balance towards bone formation.
Conclusion: The Piezo1–ZBP1 axis constitutes a novel mechano-immune switch converting physical stress into inflammation and bone resorption. Pharmacological targeting of this axis offers a bidirectional therapeutic strategy for controlling orthodontic movement and enhancing bone repair.