Wang D, Ruan X, Liu X, et al. SUMOylation of PUM2 promotes the vasculogenic mimicry of glioma cells via regulating CEBPD. Clin Transl Med. 2020;10(5):e168. doi:10.1002/ctm2.168

[Description of error]

In Figure 2g, the image of the U251 control group was inadvertently taken from an earlier draft version rather than the finalised version. Consequently, the control group image may appear to display a slightly higher apparent cell density compared with the sh-NC group, which could lead to a minor visual misinterpretation.

After carefully re-examining all original data, we confirmed that this mistake was due to the incorrect selection of a representative image for the control group. Therefore, this correction does not alter the results, statistical analyses, or conclusions of the paper.

The corrected version of Figure 2g is provided below. We sincerely apologise for this oversight and for any confusion it may have caused.

Background: Lenvatinib resistance (LR) represents a significant obstacle in hepatocellular carcinoma (HCC) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) is involved in tumour metabolic reprogramming; however, its role in LR remains unclear.

Methods: Bioinformatics analyses of public databases were integrated and validated in established LR HCC cell lines. Functional assays (CCK-8, flow cytometry and Seahorse XF analysis) were performed to assess proliferation, apoptosis and aerobic glycolysis. Post-translational modifications of AKR1B10 were characterized using co-immunoprecipitation, mass spectrometry and western blot.

Results: AKR1B10 was identified as a critical driver of resistance by establishing a metabolic positive feedback loop. Bioinformatics analyses and experimental validation demonstrated that AKR1B10 upregulation correlates with therapeutic resistance. Functional studies indicated that AKR1B10 promotes resistance by enhancing aerobic glycolysis. Mechanistically, alanyl-tRNA synthetase 1 mediates lactylation modification at AKR1B10 lysine 173 (K173), stabilizing AKR1B10 by blocking ubiquitin (Ub)-proteasomal degradation. Stabilized AKR1B10 interacts physically with lactate dehydrogenase A (LDHA), promoting LDHA phosphorylation at Y10 and accelerating glycolytic lactate production. The increased lactate subsequently induces histone H3K18 lactylation (H3K18la), which transcriptionally upregulates LDHA expression. Thus, a self-reinforcing AKR1B10–lactate–LDHA amplification circuit is formed. Clinical analyses confirmed elevated AKR1B10 expression in LR HCC patient tissues. Importantly, targeting this axis with the AKR1B10 inhibitor epalrestat (EPA) synergized with lenvatinib, overcoming resistance in xenograft mouse models and patient-derived xenograft models.

Conclusions: These findings establish AKR1B10 as both a biomarker and a therapeutic target in HCC. They reveal a novel lactylation-driven glycolytic adaptation mechanism and support the clinical translation of combined EPA–lenvatinib therapy.

Background: TROP2, a critical cell surface oncogenic signal transducer, is increasingly linked to refractory metastatic colorectal cancer (CRC) and other solid tumours. Robust lactate accumulation within metastatic niches correlates with pathological metastatic progression. Anti-TROP2 antibody-drug conjugates (ADCs) are clinically available but show limited efficacy in advanced metastatic CRC. Elucidating how TROP2 signalling orchestrates molecular and cellular programs enabling CRC metastatic progression would help improve metastasis therapies.

Methods: Tissue microarray, immunohistochemistry, and western blotting delineated TROP2's pathological role in CRC liver metastasis (CRLM). Metabolomics characterised TROP2-mediated metabolic effect. Western blot detected TROP2 responsive lactylation sites. Cell-derived xenograft (CDX), intra-splenic injection models, and patient-derived xenografts (PDX) validated TROP2 or TROP2-induced H3K18 lactylation (H3K18la) in CRLM pathogenesis and Acriflavine therapeutic response. Genome-wide H3K18la profiling was performed by ChIP-seq.

Results: Here, we identify a self-reinforcing positive feedback loop between H3K18la and TROP2 in CRC cells that drives CRC metastatic progression. We show that TROP2 is elevated during CRC metastatic process, with high TROP2 levels in liver metastases predicting increased post-therapy recurrence in two distinct cohorts. We find that H3K18la levels are upregulated in CRC cells in response to TROP2 expression level. TROP2 promotes robust lactate production via the YBX1-HIF-1α signal axis. Targeting glycolytic flux decreases H3K18 lactylation and curbs TROP2-driven CRLM colonisation and progression. Mechanistically, ChIP-seq detection reveals H3K18la deposition at a set of pro-metastatic gene promoters, promoting their expression. Crucially, TROP2-induced H3K18la is found in turn sustaining TROP2 expression, forming a positive feedback loop that further accelerated metastatic progression. Pharmacologic HIF-1α inhibition with acriflavine, an old FDA-approved agent, suppresses TROP2-high CRLM progression in multiple pre-clinical models.

Conclusions: Collectively, we establish H3K18la as a crucial epigenetic driver of TROP2-mediated CRLM progression and propose that disrupting the H3K18la–TROP2 feedback loop offers a novel therapeutic strategy against CRC metastasis.

Background: Acute respiratory distress syndrome (ARDS) frequently develops after cardiopulmonary bypass (CPB), with lung ischemia/reperfusion injury (LIRI) as a major contributing factor. However, the role of fatty acid-binding protein 4 (FABP4) in the pathogenesis of CPB-associated ARDS remains poorly understood.

Methods: Experimental LIRI models were established in vivo and in vitro to investigate the role of FABP4 in alveolar epithelial injury. Lipid droplets (LDs) accumulation, fatty acid (FA) metabolism, epithelial-mesenchymal transition (EMT), and alveolar epithelial barrier (AEB) integrity were assessed using molecular, cellular, and functional approaches. Pharmacological and genetic interventions were applied to evaluate the contribution of FABP4-mediated signaling pathways.

Results: LIRI induced autocrine FABP4 signaling in alveolar epithelial cells, leading to pronounced LDs accumulation and disruption of AEB integrity. FABP4 activation enhanced FA metabolism and promoted EMT, which played a critical role in epithelial barrier dysfunction. Mechanistically, FABP4 activated the p38 MAPK pathway, resulting in ULK1 phosphorylation, suppression of lipophagy, and subsequent LDs formation, thereby driving EMT. Inhibition of LDs accumulation effectively attenuated EMT and alleviated AEB disruption.

Conclusion: FABP4 serves as a key metabolic regulator linking lipid reprogramming to EMT and alveolar epithelial barrier disruption during LIRI. Targeting FABP4-mediated lipid metabolism may represent a promising therapeutic strategy for preventing ARDS following CPB.

Background: Long non-coding RNAs (lncRNAs) regulate macrophage inflammation and atherosclerotic plaque stability, but mechanisms need comprehensive investigations.

Methods: Whole-transcriptome sequencing was used to identify a novel human-specific lncRNA, lncAPAT (atherosclerotic plaque instability-associated transcript), in the peripheral blood of patients with coronary artery disease (CAD; n = 5) with mixed plaques on coronary computed tomography angiography (CCTA). LncAPAT was quantified using quantitative real-time polymerase chain reaction in the discovery cohort and independently validated in patients with coronary mixed plaques by CCTA (n = 22) and in patients with acute ST-segment elevation myocardial infarction (STEMI; n = 22). Myeloid cell-specific lncAPAT knock-in mice were generated and injected with recombinant adeno-associated virus of murine proprotein convertase subtilisin/kexin type 9 to induce atherosclerosis and explore the effects of lncAPAT on inflammation and plaque instability. Macrophages were cultured to evaluate lncAPAT function in vitro. Chromatin isolation by RNA purification and sequencing and RNA immunoprecipitation assays were used to identify potential targets of lncAPAT.

Results: LncAPAT expression was highly expressed in the peripheral blood of CAD and STEMI patients compared with the control individuals. Mice with myeloid cell-specific lncAPAT knock-in showed an increased plaque burden (2.7-fold), elevated macrophage counts (2.4-fold), and higher matrix metalloproteinase (MMP) expression (3.3-fold for MMP9, 2.0-fold for MMP2) in thoracic aortic plaques. In vitro, lncAPAT significantly promoted the inflammatory responses, adhesive capacity and cholesterol accumulation of macrophages, and decreased the cholesterol efflux ratio. LncAPAT interacted with the promoter of the ribosomal protein L22 gene (RPL22) and inhibited RPL22 transcription. RPL22 inhibition significantly increased the expression of inflammatory cytokines. The RPL22 protein directly interacted with monocyte chemoattractant protein-1 (MCP-1) mRNA and decreased MCP-1 expression. Furthermore, RPL22 expression in the peripheral blood was lower in CAD and STEMI patients than in control individuals.

Conclusions: LncAPAT promoted the macrophage inflammatory response by inhibiting RPL22 transcriptional activity, contributing to plaque instability.

Background: This study investigates the impact of sleep restriction (SR) on flap viability and its underlying mechanisms. It reveals that SR triggers clock rhythmic ferroptosis, which leads to impaired skin barrier function and increased flap necrosis.

Methods: A retrospective analysis of sleep quality in 344 patients undergoing flap surgery proved that SR is a risk factor for flap necrosis. Further research demonstrated that SR increases the level of ferroptosis, disrupts the circadian rhythm of ferroptosis and exacerbates flap damage in human and murine models.

Results: In order to address this clinical issue, the use of melatonin (MT)-preconditioned bone marrow mesenchymal stromal cells-derived exosomes (MEXOs) was found to enhance the therapeutic efficacy of flap repair by mitigating clock rhythmic ferroptosis. Mechanistically, MT increased m6A modification to stabilise and enhance the translation of ubiquitin-specific protease 4 (USP4) mRNA within MEXOs. USP4 delivered by MEXOs directly interacted with and deubiquitinated ARNTL, a core circadian regulator, stabilising its protein levels and suppressing ferroptosis in flap.

Conclusions: These findings identify SR-induced clock rhythmic ferroptosis as a critical pathological driver of flap failure and propose a novel exosome-based strategy targeting the USP4–ARNTL axis to enhance skin barrier integrity and flap survival, offering translational potential for clinical reconstructive surgery.

Background: Primary pulmonary sarcomas (PPS) and pulmonary sarcomatoid carcinoma (PSC) are rare and aggressive diseases that pose significant diagnostic challenges, requiring extensive sampling and comprehensive evaluation. To date, the single-cell characteristics and distinctions between these two conditions have not been thoroughly investigated.

Methods: In this study, we employed single-nucleus RNA sequencing (snRNA-seq) to characterise the cellular heterogeneity of PSC and PPS. Our analysis included 20 PSC samples, seven PPS samples and two non-malignant control samples obtained from adjacent normal tissue.

Results: Our results revealed that the majority of cells in PSC were of epithelial origin, while fibroblasts predominated in PPS. Specifically, AT2 cells, a major source of epithelial cells in PSC, underwent malignant transformation primarily through epithelial–mesenchymal transition, suggesting AT2 cells may serve as the origin of PSC. High Mobility Group AT-Hook 2 (HMGA2) expression was elevated in malignant AT2 cells of PSC and correlated with an unfavourable prognosis. Moreover, MET-mutated patients have a significantly higher expression level of HMGA2 (p < .001). In PPS, fibroblasts constituted the majority, only lipofibroblasts exhibited malignant features. A direct comparison between PSC and PPS lipofibroblasts revealed largely similar expression profiles, with the exception of an enrichment in DNA repair pathways specifically observed in PPS lipofibroblasts.

Conclusion: These findings provide novel insights of PSC and PPS at the single-cell level.

Background: Thrombosis is a common complication in paroxysmal nocturnal haemoglobinuria (PNH) patients, but primary prevention remains controversial. Identifying high-risk individuals could enable risk-stratified prophylactic anticoagulation strategies.

Methods: We analyzed clinical data from PNH patients with or without thrombosis, including MUC4 mutation status and serum complement C5b-9 levels. Complement deposition assays and a murine lower limb deep vein thrombosis model were used to investigate the role of MUC4 mutation in thrombotic risk and explore the underlying mechanism involving terminal complement activation in PNH patients. Therapeutic interventions with low molecular weight heparin (LMWH) were tested in vivo.

Results: We found that PNH patients with MUC4 mutations have a higher incidence of thrombotic events (TEs) and MUC4 mutation is an independent risk factor for TE in PNH patients. Additionally, PNH patients with acute thrombosis had elevated serum complement C5b-9 levels, and complement deposition experiments further confirmed the abnormal activation and excessive deposition of C5b-9 as the basis for the thrombotic tendency in PNH patients. By constructing a mouse model of lower limb deep vein thrombosis, we confirmed the thrombotic tendency in a PNH mouse model and that MUC4 deficiency further promoted the thrombotic phenotype of the mice. Moreover, we found that MUC4 knockdown promoted the deposition of C5b-9 on the cell surface, indicating that a lack of MUC4 expression facilitates the deposition of C5b-9. Finally, in vivo drug administration experiments demonstrated that prophylactic anticoagulation with LMWH significantly reduced both the incidence of thrombosis and thrombus length in murine models.

Conclusion: MUC4 mutations promote the thrombotic phenotype in PNH patients by increasing the deposition of terminal complement. In PNH patients with concomitant MUC4 mutations, the risk of TEs is further elevated. The potential role of early complement inhibitor therapy in reducing this heightened thrombotic risk, as well as the value of prophylactic LMWH therapy as a potential option for patients who are unable to receive complement inhibitor treatment, warrants further study and prospective validation.

Background: Adult ovarian granulosa cell tumours (GCT) are the most common subtype of ovarian sex cord-stromal tumours. Forkhead transcription factor FOXL2 is required for development and function of normal granulosa cells, including proliferation and ovarian hormone synthesis. A single somatic missense mutation in FOXL2, c.402C > G (p.Cys134Trp), has previously been identified in the majority of GCT and is a pathognomonic marker for this tumour type. NOTCH activation contributes to GCT survival in preclinical models, and NOTCH2 and NOTCH3 are critical for embryonic development of the ovary and function of the ovarian follicle. Nirogacestat is a potent, selective, noncompetitive inhibitor of gamma secretase, which inhibits NOTCH pathway signalling. Treatment of GCT with nirogacestat was predicted to inhibit granulosa cell survival.

Methods: A Phase II clinical trial was conducted to assess antitumour activity of nirogacestat in adult patients with relapsed/refractory ovarian GCT (NCT05348356). This study enrolled 53 patients; all were evaluable for efficacy and safety. Endpoints included objective response rate by Response Evaluation Criteria in Solid Tumors v1.1 and 6-month progression-free survival (PFS6). Fresh or archival tumour samples were analysed for mutational profiling.

Results: Patients received a median of 5 prior lines of therapy (range, 1–13) and a median of 3.7 months of treatment (range, 0–20 months). A decrease in tumour burden was seen in 16 (30%) patients; however, there were no confirmed objective responses. Thirty-one (58%) patients had stable disease; 18 (34%) had progressive disease. Eleven (21%) patients achieved PFS6. No correlations with disease stability were found with baseline clinical characteristics. All 3 patients who had an activating NOTCH1 mutation achieved PFS6.

Conclusions: In patients with heavily pretreated GCT, nirogacestat treatment resulted in durable disease stabilisation of at least 7 weeks for 58% of patients, with 21% achieving PFS6, including the 3 patients whose tumours had an activating NOTCH1 mutation.

Background: Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by high mortality with no specific treatments. Fibroblast growth factor 10 (FGF10) is recognized for its tissue repair and anti-inflammatory roles in injured lungs; however, its clinical relevance and mechanistic role in ARDS remain unclear.

Methods: Serum FGF10 levels were measured in patients with ARDS and analyzed for associations with clinical outcomes. An LPS-induced mouse model of acute lung injury (ALI) was used to evaluate the effects of FGF10 treatment in vivo. Single-cell RNA sequencing of lineage-traced alveolar epithelial cells (AECs) was performed to identify transcriptional changes following FGF10 administration. In vitro co-culture systems involving macrophages or neutrophils with AECs were established to investigate immune cell-specific mechanisms.

Results: We found that serum FGF10 levels were significantly reduced in ARDS patients, and this reduction correlated with poor prognosis. Moreover, FGF10 treatment alleviated lung inflammation by decreasing inflammatory cell infiltration and pro-inflammatory cytokine release in mice. Leveraging single-cell RNA sequencing of lineage tracing alveolar epithelial cells (AECs), we identified that the mRNA expression of Ripk1, Casp8, and Casp3 were decreased after FGF10 treatment. In in vitro co-culture experiments, we noticed that FGF10 did not inhibit macrophage pyroptosis. Instead, FGF10 effectively blocked the downstream RIPK1/caspase-8/caspase-3/gasdermin E (GSDME) signaling pathway in AECs. Additionally, FGF10 suppressed AMP-activated protein kinase (AMPK) activation by modulating ATP production, thereby preventing RIPK1 cleavage.

Conclusion: FGF10 alleviates acute lung injury by inhibiting AMPK-RIPK1/caspase-8/caspase-3/GSDME-mediated pyroptosis in AECs primed by distinct immune cell populations, supporting its potential as a therapeutic strategy for ARDS.

Background: The triglyceride-glucose index (TyG), a novel marker of insulin resistance, is recognised as a risk factor for multiple cardiovascular diseases. The link between its risk and aortic dissection and aortic aneurysm (AD/AA) is not well-defined. This research seeks to explore the relationship.

Methods: This study analysed 386 063 participants from the UK Biobank, a large prospective cohort, all initially free of AD/AA. The main focus was on the occurrence rate of AD/AA. Multivariate Cox regression models were used to analyse the association between the TyG index, its related parameters, and the risk of AD/AA. Association was further validated using a real-world clinical cohort from Central China Fuwai Hospital. A two-sample Mendelian randomisation (MR) analysis utilising the inverse variance weighting method was conducted to investigate the causal link between TyG and AD/AA.

Result: Among the 386 063 participants in the UK Biobank cohort, 3805 cases of AD/AA were reported. After controlling for covariates, a higher TyG index and its related parameters were associated with an increased incidence of AD/AA. The hazard ratios (HRs) were as follows: TyG (HR = 1.14, 95% CI: 1.07–1.22, p <.001), TyG-WHR (HR = 1.17, 95% CI: 1.12–1.22, p <.001), and TyG-WHtR (HR = 1.11, 95% CI: 1.06–1.16, p <.001). Association between TyG and the risk of aortic diseases was also replicated in the single-centre cohort. Two-sample MR analysis indicated strong evidence of a causal relationship between genetically predicted TyG levels and AA (OR = 1.97, 95% CI: 1.37–2.84, p <.001), while no significant association was observed with AD (OR = 0.79, 95% CI: 0.31–1.99, p = .61).

Conclusion: Through complementary epidemiological, clinical, and genetic approaches, our findings indicate that elevated TyG index represents a robust and potentially causal risk factor for aortic diseases (especially AA). These results highlight the importance of metabolic risk assessment in aortic disease prevention and emphasise the need for further mechanistic studies to understand the differential links between TyG and specific aortic phenotypes.

Background: DFNB16, the second most common genetic cause of hearing loss, is caused by mutations of the STRC gene encoding stereocilin, a protein essential for the effective functioning of outer hair cells (OHCs) as cochlear amplifiers. Strc^−/− mice, which lack stereocilin, display severe to profound deafness and constitute a relevant preclinical model for DFNB16.

Methods: Using Strc⁻/⁻ mice, we developed a gene therapy strategy based on the use of dual AAV9-PHP.eB vectors to deliver the full-length Strc cDNA. Therapeutic efficacy was assessed by evaluating stereocilin expression, OHC bundle architecture, and their attachment to the tectorial membrane, together with functional recovery using distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABR) measurements and Go/No-Go behavioral testing with psychometric analysis.

Results: Dual-AAV–mediated Strc gene delivery restored stereocilin expression, OHC bundle architecture and their attachment to the tectorial membrane, leading to the recovery of cochlear amplification and hearing to near normal thresholds, as confirmed by distortion product otoacoustic emission (DPOAE) and auditory brainstem response measurements. Behavioural assessment showed that treated Strc^−/− mice regained normal frequency discrimination, indicating a restoration of higher-order auditory processing, up to 100 days post-treatment.

Conclusion: These findings provide the first proof-of-principle that peripheral gene therapy can restore OHC function, cochlear amplification and central auditory perception in a DFNB16 model.

Background: DDB1 and CUL4-associated factor 7 (DCAF7) is a WD-repeat adaptor that recruits substrates to the CUL4DDB1 ubiquitinligase complex, but its pan-cancer relevance and mechanistic contribution to tumor progression remain unclear.

Methods: Multi-omics datasets (genomic, transcriptomic, epigenomic, proteomic and single-cell) from 33 tumor types were integrated to define DCAF7 expression, regulation, and clinical significance. Somatic alterations and copy-number variation were analysed across cohorts, and promoter methylation and RNA modification signatures were interrogated. Immune associations were assessed by computational deconvolution and checkpoint-gene profiling. Pathway and network analyses were performed to infer DCAF7-linked programmes. Mechanistic and functional validation was conducted in hepatocellular carcinoma (LIHC) cell lines (HepG2, Huh7) using DCAF7 perturbation and pharmacologic Wnt inhibition.

Results: DCAF7 was overexpressed in most cancers, consistent with copy-number gain, focal promoter hypomethylation and putative m⁶A-linked post-transcriptional regulation, whereas hypermethylation at two CpG loci predicted poor prognosis in LIHC. DCAF7 alterations, predominantly amplifications, were associated with shorter overall survival in LIHC and positively correlated with DCAF7 mRNA abundance across cohorts. Immunogenomic analyses linked high DCAF7 to CD4⁺ T-cell enrichment, broad upregulation of checkpoint genes (PD-1/PD-L1, CTLA-4, TIGIT), and increased tumour mutational burden, microsatellite instability and neoantigen load, suggesting an immune-evasive phenotype. Network and enrichment analyses converged on canonical Wnt/β-catenin, Hippo and cell-cycle programs. In vitro, DCAF7 promoted LIHC cell proliferation and migration by stabilising β-catenin via increased inhibitory Ser9 phosphorylation of GSK-3β, thereby inducing c-Myc and cyclin D1; DCAF7 knockdown or the Wnt inhibitor XAV939 attenuated these effects. Drug-response modelling further predicted increased sensitivity of DCAF7-high tumours to 17-AAG, docetaxel and alsterpaullone.

Conclusions: DCAF7 is frequently activated by genetic and epigenetic mechanisms across cancers, associates with an immunotherapy-relevant tumour immune milieu, and drives Wnt/β-catenindependent malignant phenotypes in LIHC. These findings support DCAF7 as a prognostic biomarker and a candidate therapeutic target, particularly for stratified intervention in LIHC.

Background: Colorectal adenocarcinoma (COAD) cells exploit stress-adaptation programs, such as the unfolded protein response (UPR), to survive in hostile tumour microenvironments. However, the role of specific E3 ubiquitin ligases in regulating these survival pathways remains poorly understood. We investigated Ring Finger Protein 39 (RNF39), an E3 ligase previously implicated in immune signalling, as a potential regulator of COAD progression.

Methods: We analyzed RNF39 expression using public transcriptomic datasets (TCGA, GEO) and a clinical COAD cohort via immunohistochemistry. Functional roles were assessed in COAD cell lines using shRNA knockdown, CRISPR/Cas9 knockout, and overexpression systems. In vitro assays (proliferation, invasion, colony formation) and in vivo xenograft models were employed. Mechanistic investigations included co-immunoprecipitation, ubiquitination assays, chromatin immunoprecipitation, and luciferase reporter assays to delineate the MEF2D-RNF39-RINT1 axis.

Results: RNF39 was aberrantly upregulated in COAD tissues, and its high expression correlated with poor patient survival. We identified the transcription factor MEF2D as a direct activator of RNF39. Functionally, RNF39 promoted COAD cell proliferation and invasion in vitro and tumour growth in vivo, dependent on its E3 ligase activity. Mechanistically, RNF39 directly interacted with, polyubiquitinated (K48-linked), and promoted the proteasomal degradation of RAD50-interacting protein 1 (RINT1). Consequently, RNF39 depletion stabilized RINT1, amplified the UPR and CHOP expression, and sensitized cells to ER stress-induced apoptosis. Crucially, the anti-tumour phenotypes of RNF39 loss were partially reversed by simultaneous RINT1 knockdown.

Conclusion: RNF39 acts as a pro-tumorigenic E3 ligase in COAD by driving the degradation of RINT1, thereby suppressing ER stress-induced apoptosis and promoting malignant progression. Our findings delineate a novel MEF2D-RNF39-RINT1 signalling axis that governs tumour cell adaptation to stress. Targeting RNF39 could represent a promising therapeutic strategy to overcome stress resistance in COAD.

Background: Hepatitis B virus (HBV) is clinically associated with poor prognosis in diffuse large B-cell lymphoma (DLBCL), while cellular communication in the tumour microenvironment (TME) is recognized as a critical driver of tumour progression. Nevertheless, whether HBV infection mediates DLBCL cell-immune cell crosstalk remains undefined, with the precise mechanisms and associated key molecules remaining elusive.

Methods: SsGSEA, Cox regression (univariate/multivariate), WGCNA, and Kaplan–Meier analyses identified prognostic immune subsets and miRNAs in HBV⁺ DLBCL. Dual luciferase assay, qRT-PCR, western blot, ChIP, Co-IP, flow cytometry, enzyme-linked immunosorbent assay, immunohistochemistry, and murine models were employed together to evaluate CD4⁺ T cell dysfunction in vitro and in vivo. ScRNA-seq analyses encompassed clustering, pseudotemporal trajectory, and ligand–receptor networks to decode TME dynamics.

Results: TME profiling identified diminished CD4⁺ T cell infiltration as an independent predictor of poor survival in HBV⁺ DLBCL. Mechanistically, HBx-mediated down-regulation of miR-19a-3p activated the BAMBI/Wnt signalling pathway, thereby enhancing TGF-β1 secretion and suppressing the anti-tumour activity of CD4⁺ T cells. Single-cell analysis revealed that BAMBI^high DLBCL cells engage CD4⁺ T cells via TGFB1-TGFBR2 pair, with TGFBR2 enriched in exhausted subsets of CD4⁺ T cells and shaping their dysfunctional fate. Therapeutic restoration of miR-19a-3p or blockade of TGF-β reinforced the CD4⁺ T cell anti-tumour activity and restrained the progression of HBx-overexpressing DLBCL in vivo.

Conclusions: HBx promoted TGF-β1 hypersecretion via miR-19a-3p repression-mediated Wnt/β-catenin activation, directly driving CD4⁺ T cell depletion and functional exhaustion in DLBCL. Our work provided important insights into the immune determinants of poor prognosis in HBV⁺ DLBCL, highlighting the pivotal role of CD4⁺ T cell dysfunction in driving disease progression and adverse clinical outcomes.

Background: Neoadjuvant anti-programmed cell death 1 (PD-1) immunochemotherapy has shown promising efficiency in the treatment of early-stage non-small-cell lung cancer (NSCLC), but it has not consistently yielded durable responses. Biomarkers for the prediction of efficacy are warranted.

Methods: We performed shotgun metagenomic and plasma/faecal metabolomic studies in 44 NSCLC patients who underwent neoadjuvant tislelizumab plus platinum-based doublet chemotherapy. Samples were collected at baseline and before surgical resection, and the major pathologic response (MPR) was evaluated.

Results: MPR patients showed a significantly higher gut-microbial alpha diversity, an enrichment of Ruminococcaceae, Lachnospiraceae and Clostridiales species, and an increased plasma level of tryptophan metabolites at baseline. On the contrary, non-MPR patients were characterized by enrichment of Prevotella species in faecal samples and higher plasma levels of linoleic acid metabolites. A high predictive accuracy was achieved using a small panel of differential microbial (Clostridium sp. M62/1 and Eisenbergiella tayi) or metabolomic features (linoleic acid, oxindole-3-acetic acid and quinolinic acid) with AUCs > .85.

Conclusions: The baseline characteristics of the gut microbiota and plasma metabolites could provide early predictions of the response to neoadjuvant anti-PD-1 immunochemotherapy.

Trial registration: NCT05244837.

Triple-negative breast cancer (TNBC), marked by profound immunosuppressive complexity, poses a critical challenge in therapy due to the absence of hormone receptors in its phenotype, making it unavailable for conventional therapies. The stimulator of interferon genes (STING) pathway is emerging as critical pathway translating the immunogenic ‘cold’ TNBC tumour into ‘hot’ one, thereby improving the responsiveness to immune checkpoint blockade (ICB). However, the clinical translation is still hindered by insufficient cytosolic delivery, rapid systemic degradation and tumour microenvironment-induced metabolic inactivation. This review outlines the recent advances in STING-mediated nanoparticle delivery with special emphasis on biomimetic, Trojan horse logic gate, manganese-based and redox-responsive stimuli delivery systems. Mechanistically, it integrates immune activation by ferroptosis, cuproptosis and mitochondrial DNA disruption. They synergise the amplification of type 1 interferon with dendritic cell maturation, potentiating antitumour immunogenesis. Notably, the combination with ICBs will further amplify the therapeutic potential of nanoparticles. Convergence of immunology and targeted therapies with nanoparticles opens new array for TNBC treatment. The review visualizes the clinical translation of mind maps into clinical reality, activating the innate immunity.

Pseudouridine synthases (PUS) have been implicated in various cancers, yet their roles in pancreatic cancer immunity remain unclear. Through integrative multi-omics analyses combining genomics, transcriptomics, and clinical datasets, we evaluated associations between PUS family genes and oncogenic features, including tumour microenvironment scores, immune infiltration, cancer stemness, and prognosis. Among them, PUS7 and PUS3 showed the strongest correlations with tumour-promoting phenotypes, with high PUS7 expression in PDAC predicting poor overall survival. Functional assays revealed that PUS7 overexpression markedly enhanced PDAC cell proliferation, migration, and invasion. Transcriptomic profiling demonstrated that PUS7 promotes neutrophil extracellular traps formation, identifying it as a key regulator of NET-mediated immune modulation. Single-cell RNA sequencing of orthotopic mouse models showed PUS7 overexpression reduced macrophage infiltration and skewed macrophage polarization towards the M2 phenotype while suppressing M1 polarization. We found that PUS7 reshapes the PDAC immune landscape primarily by inducing NETs, which drive macrophage polarization from M1 to M2, fostering immune suppression and tumour progression. The PUS7–NET–M2/M1 axis thus represents a novel mechanism of PDAC pathogenesis and a potential therapeutic target in this lethal malignancy.

Immune checkpoint blockade (ICB) has revolutionized tumour therapy by relieving immunosuppression and restoring effector T cell cytotoxicity. However, its clinical utility is constrained by low response rates and acquired resistance. Tumour-associated neutrophils (TANs), key players in tumour immunoregulation, have emerged as critical mediators of ICB responsiveness and resistance, highlighting the therapeutic potential of combining TAN-targeted strategies with immune checkpoint inhibitors (ICIs). This review systematically synthesizes current knowledge of neutrophils in ICB resistance from several dimensions: (1) clinical indicators of neutrophils, such as the neutrophil-to-lymphocyte ratio (NLR) and tissue TANs abundance, as predictors of ICI response and patients prognosis; (2) multifaceted TAN-involved resistance mechanisms, including direct T cell inhibition, antigen presentation impairment, function modulation of other immune cells, promotion of tumour angiogenesis, and elevation of tumour mutation burden (TMB); (3) combination therapeutic strategies targeting TAN generation/ exhaustion, recruitment, phenotypic polarization, activation, proangiogenic functions, and neutrophil extracellular traps (NETs), along with progress in related clinical trials. Combinatorial approaches integrating TAN-targeted therapies with ICIs hold substantial promise for overcoming resistance by reshaping the immune microenvironment. Elucidating neutrophil-mediated resistance mechanisms and optimizing combination strategies will pave the way for precision tumour immunotherapy.

Background: BRD7 has been confirmed to be lowly expressed in nasopharyngeal carcinoma (NPC) tissues and exerts tumour suppressive roles. However, the molecular mechanism of the downregulation of BRD7 expression and whether the strategy of activating BRD7 expression plays anti-tumour effects still needs to be clarified.

Methods: Methylation-specific polymerase chain reaction (PCR) was used to identify the methylation levels of BRD7 promoter. In vitro experiments were used to evaluate the effects of BRD7-targeted demethylation system on the malignant progression of NPC cells. Chromatin immunoprecipitation (ChIP)-qPCR experiment was employed to examine the regulatory mechanisms underlying the demethylation system. Xenograft tumour models were used to assess impact of this demethylation system on tumour growth in vivo and the anti-tumour effects of the lentivirus-mediated demethylation system in NPC.

Results: There was hypermethylation modification in BRD7 promoter, which was negatively correlated with BRD7 expression. Next, we constructed a LentiCRISPRv2/dCas9-TET1CD-sgRNAs system targeting specific methylation sites of BRD7 promoter based on five sgRNAs, and confirmed that all five sgRNA-guided CRISPR/dCas9 systems could activate BRD7 and inhibit cell proliferation to varying degrees, among which sgRNA2&sgRNA5 were the most significant. Further, we constructed NPC cell lines stably transfected with LentiCRISPRv2/dCas9-TET1CD-sgRNA2&5, and confirmed that both sgRNA2&sgRNA5 could promote the transcriptional activation by reducing its methylation, and inhibit the cell proliferation, migration, invasion and tumour growth in vivo of NPC, and the combination of them has a more significant demethylation, transcriptional activation and anti-tumour effect. In addition, BRD7 had hypermethylation modification in its promoter and decreased expression in NPC tissues, and both of them were negatively correlated, making it a potential diagnostic marker for NPC diagnosis.

Conclusions: The hypermethylation modification of BRD7 is an important mechanism leading to the inactivation of BRD7, and targeting demethylation of BRD7 inhibits the malignant progression of NPC, which might be a promising targeted therapeutic approach for treating NPC.

Background and Rationale: Synthetic lethality (SL)-based strategies hold significant promise for overcoming therapeutic resistance, a critical bottleneck in cancer treatment where cancer cells evade anticancer therapies, leading to diminished efficacy or treatment failure. The core of SL lies in exploiting tumour-specific vulnerabilities: drug-resistant cells often acquire unique genetic defects or compensatory adaptive responses, and SL strategies selectively target genes or pathways dependent on these vulnerabilities to induce specific cell death, thereby reversing resistance.

Content and Focus: This review systematically elaborates on SL mechanisms and the multi-faceted nature of tumour drug resistance, then focuses on how SL counteracts resistant phenotypes by leveraging resistant cells’ vulnerabilities. We further delineate SL applications in preclinical resistance models, highlight representative SL-related drugs and predictive biomarkers and critically analyse challenges in clinical translation.

Conclusion: By integrating mechanistic insights, preclinical validation and translational perspectives, this review aims to provide novel insights for precision therapy and a foundational reference to advance SL strategies in overcoming tumour resistance and facilitating their clinical implementation.

Backgroud: Persistent infection with high-risk human papillomavirus type 16 (HPV16) is a principal etiological factor in cervical cancer. Nevertheless, the molecular events linking HPV16-associated lesion progression to malignant transformation remain insufficiently characterized, particularly those involving vesicular trafficking and autophagy regulation.

Methods: Proteomic analysis was conducted across five stages of HPV16-associated cervical lesion progression to identify differentially expressed proteins. The expression of vesicle-associated membrane protein 7 (VAMP7) was validated in cervical tissue specimens and cellular models. Gain- and loss-of-function approaches were employed to assess the effects of VAMP7 on cellular proliferation, migration, invasion, and apoptosis. Autophagic activity was evaluated by LC3 lipidation, autophagosome accumulation, and analysis of SNARE complexrelated proteins. The in vivo effects of VAMP7 were examined using xenograft tumor models.

Results: VAMP7 demonstrated dynamic expression changes during cervical lesion progression, characterized by decreased expression in HPV16-positive non-malignant tissues and a gradual increase with disease severity, reaching the highest levels in advanced cervical cancer. Functionally, VAMP7 enhanced proliferation, migration, and invasion while inhibiting apoptosis in cervical cancer cells, whereas distinct effects were observed in non-tumor cervical epithelial cells. Mechanistically, VAMP7 regulated autophagic flux through modulation of SNARE-mediated vesicle fusion, resulting in altered autophagosome accumulation and autophagy-related signaling. In xenograft models, VAMP7 overexpression significantly promoted tumor growth and increased the expression of autophagy-associated markers.

Conclusion: These data indicate that dysregulation of VAMP7-mediated autophagy contributes to cervical carcinogenesis in an HPV16-associated context. VAMP7 may represent a potential therapeutic target for the treatment of cervical cancer.

Angiogenesis, driven by the vascular endothelial growth factor (VEGF)/VEGFR signalling axis under hypoxic conditions, is one of the hallmarks of ovarian cancer (OC), contributing to tumour progression, metastatic dissemination and immune evasion. Hypoxia-induced angiogenic signalling sustains tumour growth and shapes an immunosuppressive tumour microenvironment, while homologous recombination deficiency (HRD) has been associated with increased tumour hypoxia and pro-angiogenic signalling. Conversely, VEGF pathway inhibition may exacerbate DNA damage and modulate immune cell trafficking, providing a strong biological rationale for synergy between anti-angiogenic agents, PARP inhibitors (PARPi), and immune checkpoint inhibitors. Bevacizumab, a humanised monoclonal antibody targeting VEGF-A, represents a pivotal therapeutic agent in OC management by inhibiting tumour angiogenesis and inducing transient vascular normalisation. Its clinical efficacy has been demonstrated as maintenance therapy in the first-line setting, alone or in combination with PARPi for HRD-positive disease, and in the recurrent setting both in platinum-sensitive and platinum-resistant disease. Despite these benefits, variability in patient response highlights the unmet need for validated predictive biomarkers. Circulating, tissue-based and molecular biomarkers have been investigated, including angiogenic factors (Tie2/Ang1 axis, interleukin-6 [IL-6] and chitinase-3-like protein [YKL-40]), VEGF-A isoforms, microvessel density, EGFR/ADAM17 signalling, angiomiRs and transcriptional subtypes with mesenchymal and proliferative phenotypes showing greater sensitivity to anti-angiogenic strategies. Although HRD status holds prognostic relevance and selected microRNAs show emerging potential, no biomarker has yet been validated to predict benefit from bevacizumab in clinical practice. Translational analyses from the MITO16A/MaNGO OV-2 program, highlight challenges such as assay standardisation, multiplicity correction and external validation, while identifying tumour immune infiltration patterns, TP53 mutation classes and composite HRD assessments as areas of further investigation. In conclusion, bevacizumab remains an integral component of OC treatment. Future progress will depend on biomarker-driven, prospectively designed clinical trials and the integration of multi-omic data and machine learning approaches to enable precision application of anti-angiogenic strategies, maximising clinical benefit while minimising toxicity.

Background: In colorectal cancer (CRC), innate lymphoid cells (ILCs) play a vital role in preserving and modulating immune homeostasis within the intestinal environment. However, the origins and diverse functions of ILCs in CRC remain poorly understood, making it difficult to clarify how these cells contribute to disease progression and influence therapeutic efficacy.

Methods: Single-cell RNA sequencing (scRNA-seq) generated an atlas of ILCs from multiple tissues (bone marrow, blood, and intestine), revealing their origins, heterogeneity, and plasticity. Spatial transcriptomics (ST) and immunofluorescence (IF) defined their specific cellular neighbourhoods within the tumour microenvironment. In vitro co-culture assays were performed to validate the regulatory role of ILC2s in B cell maturation. Bulk RNA sequencing and flow cytometry were employed to assess the survival and therapeutic response potential of ILCs.

Results: Intestinal ILCs have two distinct origins: ILC3-CD83 cells derived from the fetal gut, which persist into adulthood; and ILC2 and ILC3-S100A4 cells that might originate from the bone marrow and migrate through the circulation to colonise intestinal tissues. The tissue-resident ILC3 subsets exhibited diverse functional roles in CRC. Specifically, trajectory analysis showed that ILC3s differentiated into either stress-responsive ILC3-HSPA1B cells or cytotoxic ILC1/NK cells in CRC. Additionally, by using spatial transcriptomics analysis combined with functional assays, we found that bone marrow-derived ILC2s preferentially localise in tertiary lymphoid structures (TLSs), where they likely support B cell maturation. Notably, higher ILC2 abundance correlated with better clinical outcomes and greater therapeutic benefit.

Conclusions: This study reveals the distinct origins and functional heterogeneity of intestinal ILC subsets in CRC. The enrichment of bone marrow-derived ILC2s in TLSs, where they likely support B cell maturation, is associated with improved prognosis and favourable immunotherapy response, which may serve as biomarkers for survival and therapeutic efficacy in CRC.

Background: O-linked N-acetylglucosamine protein modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification frequently upregulated in cancers. Autophagy, a lysosome-dependent recycling pathway, plays a context-dependent dual role in tumorigenesis and therapy resistance. Emerging evidence reveals intricate crosstalk between these two processes, positioning the O-GlcNAcylation-autophagy axis as a critical regulator of cancer cell adaptation.

Main Topics: This review systematically delineates the multidimensional mechanisms by which O-GlcNAcylation regulates distinct stages of autophagy initiation, maturation, and fusion across various cancer types. We detail how O-GlcNAcylation targets core autophagy machinery, including the ULK1 complex, LC3 lipidation system, and SNARE fusion proteins, and modulates key signaling hubs like mTOR and AMPK. Furthermore, we integrate this molecular regulation with the stage-specific pro-tumor or tumor-suppressive functions of autophagy, highlighting how O-GlcNAcylation remodels autophagic flux to promote metabolic reprogramming, stress survival, and therapeutic resistance.

Conclusions: The O-GlcNAcylation-autophagy axis represents a promising therapeutic target. Combining small-molecule inhibitors of O-GlcNAc cycling enzymes (OGT/OGA) with autophagy modulators offers a novel strategy to overcome tumor drug resistance. Future research must address the heterogeneity of this regulatory network across cancer types and developmental stages to advance precision oncology interventions.

Keypoints:

Background: Elevated lactate is associated with vascular endothelial dysfunction, a factor that can contribute to organ failure in sepsis. However, the specific mechanisms involved have yet to be fully elucidated. Here, we investigated the role of enolase 1 (ENO1) lactylation in modulating the functions of endothelial cells (ECs) in sepsis pathogenesis.

Methods: The septic mouse model was established using two methods: cecal ligation and puncture (CLP) and intraperitoneal injection of LPS. AAV-ENO1 shRNA was administered to ablate ENO1 in vascular endothelial cells of mice. Tail vein injection of .5% Evans Blue Dye (EBD) was utilised to assess microvascular permeability in septic mice. Post-translational modification (PTM) mass spectrometry was employed to detect key proteins undergoing lactylation in endothelial cells. Additionally, CCK-8 assay, Transwell assay, and scratch wound healing assay were performed to evaluate the fundamental functions of ECs. Further investigations were conducted through Western blotting, Co-immunoprecipitation (CO-IP), RT-qPCR, RNA immunoprecipitation (RIP) and RNA sequencing to examine genes/proteins involved in vascular endothelial injury and their interactions.

Results: We found that elevated lactate in sepsis promoted the lactylation of ENO1 at the K71 residue, facilitated by the increased activity of the lactyltransferase P300. This modification reduced the binding of TRIM21 mRNA to ENO1, thereby preventing its degradation by limiting the recruitment of CNOT6. Consequently, the stability and expression of TRIM21 mRNA were enhanced. Elevated TRIM21 subsequently binds to vascular endothelial-cadherin (VE-Cadherin), promoting its ubiquitination and degradation, disrupting endothelial adherens junctions (AJs) and increasing endothelial permeability. Targeting the lactylation of ENO1 at K71 with a specific inhibitory peptide alleviated endothelial injury and improved survival rates in septic mice.

Conclusions: These findings suggest that ENO1 lactylation plays a pivotal role in vascular endothelial dysfunction during sepsis. Inhibiting lactylation may offer a therapeutic strategy for sepsis treatment.

Background: Key biological processes underlying health and disease-including electron transfer, redox regulation, and radical-mediated signaling-are fundamentally governed by quantum-mechanical principles. These processes are central to mitochondrial function, metabolism, and cellular signaling, yet their biomedical implications have remained difficult to address using classical computational approaches.

Rationale: Recent advances in quantum computing, quantum sensing, and quantum machine learning enable direct simulation and measurement of quantum phenomena in biologically relevant systems. Hybrid quantum-classical algorithms, such as the Variational Quantum Eigensolver and Quantum Phase Estimation, now provide first-principles access to redox potentials, electronic couplings, and spin-dependent reactions that are directly linked to disease mechanisms. These developments establish the foundation for quantum biomedicine as a translational framework bridging molecular physics and clinical medicine.

Content: This review synthesizes current progress in the application of quantum technologies to biomedicine, emphasizing translational relevance. We discuss quantum-informed modeling of cancer metabolism and redox rewiring, protein misfolding in neurodegenerative diseases, immune and inflammatory signaling, infectious disease mechanisms, and drug discovery. We further propose a Quantum-Experimental-Clinical (QEC) pipeline that integrates quantum simulations with experimental validation and multi-omics clinical data, enabling mechanistic interpretation of disease phenotypes and identification of redox- and spin-sensitive therapeutic targets.

Conclusion: Quantum biomedicine introduces a new mechanistic layer that links electronic-scale processes to clinical phenotypes. While current implementations are constrained by NISQ-era hardware, rapid advances in quantum algorithms and sensing technologies position quantum approaches as emerging tools in precision and translational medicine. Strategic integration of quantum methods with experimental and clinical workflows may accelerate biomarker discovery and therapeutic development.