While band alignment engineering will facilitate charge separation and channel current modulation in heterojunctions, its application in organic photoelectrochemical transistors (OPECT) is hindered by a limited understanding of interfacial photogating dynamics. To address this limitation, we engineered a chemically reconfigurable heterojunction photogate, denoted as BiVO4@UiO-66-CdS QD, which consists of electrospun BiVO4 nanofibers combined with a porous UiO-66(Zr) framework loaded with CdS QD. The zero-bias band alignment and charge-transfer route in the BiVO4@UiO-66-CdS QD heterojunction were investigated using H2O2 as a photoelectronic modulator. Through H2O2-triggered valence changes and in situ band reconstruction, we achieved dynamic reversal of photocurrent polarity and switching of dominant photogenerated species from ∙O2- to ∙OH. We demonstrated this concept by applying the built-in H2O2 response to detecting formamidopyrimidine-DNA glycosylase (FPG) at the heterostructure-based OPECT photogate. A target-triggered rolling circle amplification strategy was used to produce long DNA scaffolds for immobilizing glucose oxidase. Enzymatically produced H2O2 causes oxidative modifications to the UiO-66-CdS QD interface, dynamically altering its band structure and increasing the transistor channel current. The freestanding heterojunction allows for dense and aggregation-free attachment of CdS QD, providing a plentiful supply of photogenerated electrons. By merging enhanced photoconductive gain with H2O2 responsive dynamic band modulation, the developed OPECT biosensor demonstrates outstanding sensitivity for FPG, with a detection limit of 2.79 × 10-6 U·μL-1 and a wide linear range from 10-5 to 1 U·μL-1. This study shows that moving from static heterojunctions to dynamically tunable interfaces opens the door to a new generation of adaptive, high-performance OPECT biosensors.

Neurotrophic tyrosine receptor kinase 2 (NTRK2/TRKB) demonstrates oncogenic roles across cancers, with notable significance in gliomas where its overexpression is linked to aggressive clinical phenotypes. Lucitanib (AL3810), a multi-target tyrosine kinase inhibitor, shows unexplored potential for treating NTRK2-driven gliomas. This study employed an integrated approach combining pan-cancer analysis, computational drug screening, and experimental validation to systematically evaluate the oncogenic function of NTRK2 and the therapeutic efficacy of Lucitanib. Multi-omics analysis across 32 cancer types using TCGA/GTEx/CPTAC datasets revealed NTRK2 overexpression in gliomas (GBMLGG/LGG), correlating with poor prognosis (p < 0.01) and implicating AKT signaling and immune microenvironment modulation. Structure-based virtual screening of 26,996 compounds against NTRK2 identified Lucitanib as a high-affinity binder (ΔG < -8 kcal/mol), forming stable interactions with key residues (MET-636, PHE-633), further validated by 500 ns molecular dynamics simulations. In vitro experiments using U251MG glioblastoma cells and primary astrocytes demonstrated that Lucitanib significantly inhibited proliferation (p < 0.001), suppressed invasion and migration via MMP9 downregulation (p < 0.001), and induced apoptosis through Bcl-2/Bax modulation (p < 0.001). Its efficacy was intermediate between methotrexate and the selective NTRK2 inhibitor ana-12. Mechanistically, Lucitanib targeted the NTRK2-AKT-MMP9 axis while preserving immune effector functions. These findings establish NTRK2 as a viable therapeutic target in gliomas and highlight Lucitanib as a novel multi-mechanistic inhibitor with balanced efficacy and favorable pharmacokinetic properties, supporting its further development for clinical translation in NTRK2-overexpressing gliomas.

Background Deep vein thrombosis (DVT) is a common and clinically significant vascular disorder characterized by abnormal thrombus formation in the peripheral venous system. Si-Miao-Yong-An Decoction (SMYAD), a classic traditional Chinese medicine formula with heat-clearing and detoxifying properties, has been widely used in clinical treatment of DVT, yet its precise molecular mechanisms remain unclear. Purpose To demonstrate that SMYAD alleviates DVT by suppressing vascular endothelial ferroptosis via regulation of N-acetyltransferase 10 (NAT10) mediated N4-acetylcytidine (ac4C) modification. Methods The therapeutic efficacy of SMYAD was evaluated by Murine Doppler Ultrasound, hematoxylin and eosin staining, as well as analyses of ferroptosis indicators and inflammatory factors. To elucidate the regulatory mechanism of SMYAD on NAT10, we performed ultra-high performance liquid chromatography-tandem mass spectrometry, network pharmacology analysis, cellular thermal shift assay, molecular docking and surface plasmon resonance analysis. Furthermore, various assays were performed to evaluate ferroptosis-related parameters, including cellular iron content, lipid reactive oxygen species levels, ac4C dot blotting, qRT-PCR, and western blotting. Results After treatment with SMYAD, ac4C modification and NAT10 mRNA and protein levels in vascular tissues were significantly reduced. Containing serum of SMYAD could inhibit the mRNA and protein levels of NAT10, thereby reducing the mRNA and protein levels of Heme oxygenase 1 (HMOX1), and effectively alleviate ferroptosis. The research further confirmed that endothelial-specific knockout of NAT10 mimicked the protective effects of SMYAD. In addition, we identified kaempferol and calycosin as the bioactive constituents of SMYAD, which bind synergistically to NAT10 and downregulate ac4C modification of HMOX1. Conclusion This finding reveals a novel mechanism by which SMYAD exerts anti-thrombotic effects, offering a scientific rationale for its clinical application and demonstrating its therapeutic potential in targeting NAT10-regulated ac4C modification of HMOX1 against DVT.

Ovarian cancer (OC) ranks as the second leading cause of gynecological cancer-related mortality worldwide. The 5-year survival rate is substantially improved to 75% for patients diagnosed at early stages. However, the lack of obvious early clinical symptoms, together with the limited sensitivity, specificity, and resolution of conventional diagnostic modalities, results in early diagnosis of OC being particularly unenviable. Therefore, developing reliable and sensitive strategies for the detection of OC in early stages is an imperative requisite. Biomarkers that are aberrantly expressed in OC cells and tissues provide fascinating targets for early diagnosis. Accurate visualization of these specific biomarkers enables sensitive discrimination of OC in early stages. Among various analytical approaches, fluorescence imaging technology has emerged as a highly promising strategy for biomarkers precise detection, owing to its high sensitivity, excellent spatio-temporal resolution, real-time and noninvasive imaging. In this review, we comprehensively summarize recent advances in molecular fluorescent probes for the detection of OC biomarkers both in vitro and in vivo systems. Particular emphasis is placed on probe design strategies, chemical structures, sensing mechanisms, and biological applications. Moreover, current challenges and future opportunities in the rational design and clinical translation of molecular fluorescent probes for early OC diagnosis are also highlighted.

Necroptosis is a precisely regulated form of programmed cell death (PCD) that exhibits necrotic morphology while being orchestrated receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed lineage kinase domain-like pseudokinase (MLKL). In tumor biology, necroptosis plays a context-dependent dual role: it can suppress tumor progression by inducing immunogenic cell death (ICD) and activating anti-tumor immune responses; yet it may also promote tumor progression and immunosuppression by triggering inflammatory responses. Emerging evidence indicates that small molecule compounds, natural products, and nanomedicine technologies can effectively induce necroptosis in tumor cells, providing opportunities to overcome traditional chemotherapy resistance and enhance anti-tumor immunity. However, clinical translation faces numerous challenges, including frequent downregulation of key necroptotic proteins, the lack of robust predictive biomarkers, and potential tumor-promoting effects. This review offers an integrative perspective linking necroptosis molecular mechanisms, dual functional outcomes, and therapeutic strategies, highlighting both opportunities and risks. By providing mechanistic insights and a framework for rational design of necroptosis-based interventions, this work aims to guide future research toward effective and safe anticancer therapies. Schematic illustration of the mechanisms, dual roles in tumor therapy, and inducers of necroptosis.

Deep vein thrombosis (DVT) is a prevalent vascular disorder characterized by aberrant coagulation within the deep venous system, and the roles of RNA-binding proteins (RBPs) in its pathogenesis remain largely undefined. Herein, using a murine inferior vena cava (IVC) stenosis model, we identify RNA-binding motif single-stranded interacting protein 1 (RBMS1) as a previously unrecognized regulator of DVT progression via the modulation of vascular endothelial cell (VEC) autophagy. By utilizing endothelial cell-conditional Rbms1 knockout mice, we demonstrate that RBMS1 deficiency exacerbates thrombus formation and impairs VEC function. Mechanistically, RBMS1 associates with autophagy-related 3 (ATG3) mRNA through its 3'-untranslated region (3'-UTR) and enhances its stability, thereby promoting autophagic flux in VECs. RBMS1 depletion destabilizes ATG3 mRNA, leading to suppressed autophagy and compromised endothelial homeostasis. Conversely, ATG3 overexpression rescues autophagy impairment and mitigates thrombotic phenotypes upon RBMS1 depletion. Collectively, our findings in the IVC stenosis-induced DVT model demonstrate that RBMS1 regulates ATG3 to maintain vascular endothelial integrity, providing a mechanistic basis for further evaluation of RBMS1 in DVT intervention.

Ovarian cancer (OC) manifests the second deadliest gynecologic malignancy and shows severe conventional therapies-resistance, underscoring the urgent need for new therapeutic interventions. Disulfidptosis, caused in solute carrier family 7 member 11 (SLC7A11)-overexpressing (SLC7A11high ) cancer cells under glucose deficiency, has emerged as an appealing alternative approach. Herein we identified the significantly high expression of SLC7A11 in OC, and demonstrated that disulfidptosis induced by 6aminonicotinamide (6-AN) effectively kill SLC7A11high OC cells. Hence, to enhance the therapeutic effect of 6-AN, we engineered a novel nanodrug, FA-L@AI, utilizing folic acid (FA)-modified liposome, and also illustrated the detailed therapeutic mechanism. Upon exposed to FA-L@AI, SLC7A11high OC cells endured internal nicotinamide adenine dinucleotide phosphate (NADPH) pools deleting, which leads to cystine accumulations. The elevated cystine levels resulted in disulfide bonds formation in actin cytoskeletal protein, ultimately triggering disulfidptosis. FA-L@AI nanoparticles exhibited an impactful suppression of tumor cells growth through 6-AN-induced disulfidptosis both in vitro and in vivo . Consistently, mRNA transcriptomic analysis further elucidated the underlying mechanism of disulfidptosis. Altogether, our work displays a unique strategy mediating disulfidptosis for OC specific therapy. (c) 2026 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

A novel dual-polarity switching photoelectrochemical-electrochemiluminescence (PEC-ECL) dual-signal biosensor has been developed to detect cancer-related gene (TP53) in biofluids, addressing the limitations of conventional PEC systems that typically operate in a unidirectional mode, making them susceptible to interference and lacking error correction mechanisms. The new platform utilizes self-supporting N-doped TiO2 nanofibers synthesized via electrospinning to function as an anodic PEC signal generator. Integrating gold nanoparticles (AuNPs) into the N-TiO2 nanofibers forms a Schottky junction, enhancing hot electron transfer through the localized surface plasmon resonance (LSPR) effect of AuNPs, allowing cathodic photocurrent generation under visible light. The detection mechanism is further enhanced by a TP53-triggered rolling circle amplification (RCA) reaction, which produces DNA-CdS quantum dot (QDs) nanostrings that hybridize with N-TiO2@Au, creating semi-encapsulated heterojunctions (N-TiO2@Au@CdS) that significantly amplify the anodic photocurrent and reinstate the anodic "on" PEC state. Simultaneously, the proposed heterojunction generates a strong ECL signal in the presence of S2O82-. The dual-polarity switching capability allows for effective differentiation of the target from coexisting redox disruptors, enhancing detection reliability. The synergistic effects of the extended DNA scaffold from RCA programmed CdS QDs and the strong LSPR effect of AuNPs create high-density carriers with high energy, resulting in enhanced and reproducible PEC and ECL signals. The biosensor achieves detection limits of 0.064 fM for PEC and 1.66 fM for ECL, with excellent stability and applicability in real samples, providing a robust platform for diagnosing and prognosing TP53-related diseases.

Alzheimer's Disease (AD) is a neurodegenerative condition marked by cognitive decline and memory loss, with ferroptosis, an iron-dependent form of regulated cell death, emerging as a contributing factor. This study explored the potential modulatory effects of key components of the traditional Chinese medicine (TCM) formula Linggui Zhugan Decoction (LZD) on microglial ferroptosis in AD, focusing on IL-17 and TNF signaling pathways. Using single-cell RNA sequencing, we observed alterations in microglial populations and ferroptosis-related gene expression in AD mice. Network pharmacology and in vitro experiments indicated that LZD components might influence ferroptosis-related pathways, coinciding with reduced IL-17 and TNF levels in Aβ1-42-treated microglia. In vivo, LZD administration was associated with improved behavioral outcomes and modulation of ferroptosis markers. Although our findings suggest a correlation between LZD treatment and attenuation of ferroptosis-associated pathology, further mechanistic validation is necessary to establish causal links. This study provides preliminary evidence supporting the therapeutic potential of TCM in AD via inflammatory pathway modulation.

Fucoidan, a sulfated polysaccharide, demonstrates many biological activities. It has found extensive applications across medicine, food, cosmetics, and other industries. Recent investigations have highlighted that low molecular weight fucoidan (LMWF) possesses enhanced bioavailability and greater biological efficacy than its high molecular weight counterpart. The reduced molecular size facilitates improved absorption and augments several physiological activities, particularly its antioxidant, anti-tumor, and hypoglycemic properties. As a result, strategies for fucoidan degradation hold significant scientific and practical relevance. This review provides an overview of the primary strategy for fucoidan degradation, encompassing physical, chemical, and biological methods, and evaluates the strengths and limitations of each approach. Among these, biodegradation emerges as a promising technique, offering advantages such as environmental sustainability, high specificity, product uniformity, and gentle reaction conditions. The LMWF shows considerable potential for use in medical and food-related applications, and its production through biodegradation supports broader goals of environmental conservation and sustainable development.

Macrophage polarization represents a fundamental plasticity process within innate immunity, profoundly influencing tissue homeostasis and disease progression. Based on developmental origins, macrophages are categorized into tissue-resident macrophages and monocyte-derived macrophages, which collectively form a dynamic host defense network. Notably, the functional states of macrophages exist along a continuum, extending beyond the classical pro-inflammatory (M1) and anti-inflammatory/reparative (M2) dichotomy. These states are dynamically shaped by spatiotemporally heterogeneous microenvironmental signals and coordinated through intricate molecular networks. Key signaling pathways guide polarization directions. Metabolic reprogramming, where M1 polarization relies on glycolysis and the pentose phosphate pathway while M2 polarization favors oxidative phosphorylation and fatty acid oxidation, not only supplies energy but also generates regulatory metabolites. Furthermore, epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, contribute to stabilizing polarized phenotypes. These mechanisms are interconnected, forming feedback loops that collectively sculpt macrophage functional diversity. Dysregulated polarization underlies numerous diseases. In response, therapeutic strategies targeting macrophage polarization are rapidly emerging. These include pharmacological interventions using small molecules and metabolic modulators to reprogram cell phenotypes, immunotherapies such as CAR-M macrophages or exosome-mediated reprogramming to remodel immune microenvironments, and precision regulation through gene editing or epigenetic modifications. Although innovations like single-cell omics, spatial transcriptomics, computational modeling, and synthetic biology are advancing the field, clinical translation still faces challenges including off-target effects, inefficient delivery, microenvironmental dependency. Future research must integrate multi-omics data to develop individualized therapies, further investigate the stability and plasticity of polarization states, and leverage smart materials and advanced model systems to advance precision immunotherapeutics.

Unexplained recurrent spontaneous abortion (URSA) is a distressing pregnancy complication that seriously threat to women's reproductive health. Trophoblast pyroptosis was involved in the occurrence of URSA, but the potential mechanism remains unclear. In this work, we found CASP1 transcription and the level of pyroptosis were significantly elevated in the villous tissues of URSA patients. Suppression of cell pyroptosis by Gasdermin-D (GSDMD) or Caspase-1 inhibitors can reduce embryo resorption rate of URSA mice, while Caspase-1 over-expression in normal pregnant (NP) mice can aggravate embryo resorption. Meanwhile, a pronounced decline in the expression of microRNA-126-5p (miR-126-5p) was found in URSA patients, which was inversely related to CASP1 expression. Over-expression of miR-126-5p restrained trophoblast pyroptosis via inhibiting Caspase-1/GSDMD signaling pathway by direct binding to 3'-UTR of CASP1. Moreover, experiments in vivo substantiated that up-regulation of miR-126-5p effectively suppressed Caspase-1-mediated pyroptosis in placental tissue and significantly reduced embryo resorption rate. Collectively, these results underscored that diminished miR-126-5p expression plays a crucial role in URSA by enhancing trophoblast pyroptosis through activating Caspase-1/GSDMD signaling pathway. As a result, miR-126-5p shows significant promise as a possible biomarker for diagnosis and treatment of URSA.

Precise manipulation of interfacial charge carrier transport is essential for developing high-performance photoelectrochemical (PEC) biosensors with minimal background and high anti-interference capability in complex matrices. In this work, we present a novel low-background PEC biosensing platform capable of programmable switching of carrier transfer direction for the sensitive detection of PARP-1 in cancer tissues. The sensing architecture is based on freestanding plasmonic Schottky junctions formed by integrating Au nanoparticles into electrospun BiVO4 nanofibers. These junctions not only invert the inherent carrier transport direction but also suppress the background photocurrent to nearly zero through localized surface plasmon resonance effects. Upon target recognition, PARP-1 binds to thiol-modified double-stranded DNA (SH-dsDNA) and catalyzes the transfer of biotinylated ADP-ribose from NAD+, yielding SH-dsDNA-PARP-1 copolymers. Subsequent introduction of streptavidin-conjugated single-stranded DNA triggers hyperbranched rolling circle amplification, generating elongated DNA templates that selectively capture complementary DNA-functionalized CdS quantum dots (QDs). Capitalizing on the intrinsic sulfhydryl groups of the copolymer, high-density CdS QDs are assembled via multivalent Au-S bonds, forming a dual-template structure comprising the PARP-polymer conjugate and a dendritic DNA scaffold. This design enables programmable QD organization, facilitating one-to-many cascaded signal amplification and programmable switching of carrier transfer direction. By combining the near-zero background of BiVO4@AuNPs with the dramatically enhanced cathodic photocurrent from the densely grafted CdS QDs, the constructed "On-Off-super On" biosensor achieves an exceptional detection limit of 4.48 × 10-7 U·μL-1 for PARP-1 over a broad linear range in lung cancer tissue. This study offers a universal strategy to be used for clinical diagnosis and PARP-1 inhibitor research.

Acute lung injury (ALI) is a life-threatening inflammatory disease of the respiratory system, characterised by high mortality rates and lack of effective clinical interventions. Emerging evidence suggests that traditional Chinese medicine (TCM) formulations may offer therapeutic benefits in managing inflammatory respiratory diseases. Jinbei decoction (JBD), a 12-herb TCM preparation currently used for pulmonary fibrosis, has shown preliminary therapeutic potential in ALI; however, mechanistic studies remain limited. This study systematically evaluated JBD's therapeutic efficacy and elucidated its molecular mechanisms in LPS-induced ALI. Survival analysis demonstrated that JBD significantly improved survival rates in a concentration-dependent manner, while histopathological evaluation revealed a marked reduction in pulmonary tissue damage. These effects were further supported by significant decreases in circulating levels of major pro-inflammatory cytokines, such as TNF-α, IL-6 and IL-1β. Network pharmacology analysis identified 111 molecular targets associated with ALI pathogenesis influenced by JBD components, highlighting the regulatory effect on inflammatory signalling pathways in macrophages as the key intervening mechanism. Specifically, JBD suppressed LPS-induced inflammatory responses by inhibiting ERK phosphorylation and blocking IKKα/β activation, thereby preventing NF-κB-dependent cytokine production in macrophages. Notably, astrapterocarpan was identified as the primary bioactive constituent of JBD through integrated network pharmacology and biochemical analyses. It was found to directly destabilise TRAF6 protein and to exhibit therapeutic efficacy comparable to that of dexamethasone in promoting histological recovery. In vivo experiments further confirmed that JBD significantly reduced TRAF6 expression in murine models, reinforcing the conclusion that its therapeutic effects are predominantly mediated by astrapterocarpan. Collectively, these findings suggest that JBD functions as an agent capable of regulating macrophage polarisation and mitigating cytokine storm through TRAF6-dependent signalling pathways, thereby providing a mechanistic basis for its potential clinical application in inflammatory lung diseases.

Microbial secondary metabolites have long served as a key source of natural product-based drugs. This study evaluates the antibacterial, antibiofilm, and antioxidant activities of endophytic bacteria derived from dandelion, focusing on their effects against multidrug-resistant (MDR) clinical isolates. In total, 33 endophytic bacteria strains were isolated from Taraxacum ohwianum, representing 15 genera. Among these, 13 exhibited antibacterial activity, with 6 demonstrating efficacy against MDR clinical isolates. The endogenous strain Bacillus velezensis DR8 showed strong antibacterial activity against all three MDR strains tested and exerted inhibitory effects on the biofilm formation and dispersal of methicillin-resistant Staphylococcus aureus. Genome sequencing and antibiotics and secondary metabolite analysis shell analysis revealed that this strain harbors 12 biosynthetic gene clusters (BGCs) associated with secondary metabolite production. Of these, seven BGCs exhibited ≥ 80% similarity to known clusters, suggesting the potential to synthesize surfactin, difficidin, fengycin, bacillaene, macrolactin H, bacilysin, and bacillibactin. Overall, these findings indicate that endophytic bacteria from dandelion are a potential source of antibacterial compounds and biofilm formation inhibitors.

BackgroundDeep vein thrombosis (DVT) is a venous reflux disorder caused by dysregulated coagulation, with macrophage inflammatory responses being critical for its progression. T-cell immunoglobulin and mucin domain containing 4 (Tim-4) is known as a key regulator of macrophage function and inflammation. However, its involvement in DVT remains completely unclear.MethodsTim-4 expression was comprehensively assessed in peripheral blood mononuclear cells from DVT patients and inferior vena cava-associated macrophages in both clinical specimens and murine DVT models using integrated approaches including single-cell RNA sequencing, immunofluorescence, flow cytometry, quantitative PCR, and Western blot. Macrophage-specific Tim-4 knockout mice (LysM-Cre; Tim-4fl/fl) and littermate controls (Tim-4fl/fl) were constructed to investigate the role of macrophage Tim-4 in DVT. The interaction between Tim-4 and CK2β was verified by mass spectrometry and co-immunoprecipitation. The lncRNF219-3:1/miR-93-5p/Tim-4 regulatory axis was validated through RNA pull-down, RNA antisense purification, and luciferase reporter assays.ResultsTim-4 was significantly downregulated in DVT-associated macrophages, correlating with elevated proinflammatory cytokine levels. Macrophage-specific Tim-4 knockout aggravated DVT progression both in vitro and in vivo. Mechanistically, Tim-4 directly bound casein kinase 2β (CK2β) regulatory subunit, suppressing CK2 holoenzyme activity and subsequent NF-κB pathway activation (pP65 and pIκBα). Notably, pharmacologically blocking CK2 activation or the NF-κB pathway abolished the pro-thrombotic effects of Tim-4 deficiency. Furthermore, we identified a novel ceRNA network wherein lncRNF219-3:1 acted as a miR-93-5p sponge to indirectly upregulate Tim-4 expression, thereby enhancing anti-inflammatory macrophage responses and attenuating thrombus formation.ConclusionsOur findings demonstrate that macrophage Tim-4, regulated by lncRNF219-3:1/miR-93-5p axis, functions as a critical suppressor of DVT through hijacking and sequestering CK2β to dampen NF-κB mediated inflammation. The study unveils novel immunomodulatory mechanisms in DVT pathogenesis and highlights Tim-4 and its regulatory network as potential therapeutic targets for DVT in clinic.

High-grade serous ovarian cancer (HGSOC) exhibits poor prognosis due to late diagnosis, chemoresistance, and limited responses to immune checkpoint inhibitors. Although tumor‐infiltrating CD8+ T cells correlate with improved survival, current prognostic models remain inadequate. Thus, robust biomarkers linked to CD8+ T cell activation are urgently needed to guide clinical management. Transcriptomic and clinical profiles from 874 late-stage HGSOC patients were analyzed via single-sample gene set enrichment analysis for immune infiltration and weighted gene co-expression network analysis to identify CD8+ T cell-associated genes. An integrative machine learning approach was employed to develop a CD8⁺ T cell-associated immune prognostic signature (CIPS), which was then validated across multiple independent cohorts and benchmarked against 56 published models. CIPS was further characterized using single-cell RNA-seq analysis. The resulting 10-gene signature independently predicted overall survival in all cohorts and consistently surpassed most clinicopathological variables and comparator models. Low-risk patients exhibited significantly enhanced CD8+ T cell and cytotoxic gene scores, correlating with better responses to chemotherapy and immunotherapy. CIPS inversely correlated with tumor-mutation burden, BRCA1/2 mutations and homologous-recombination deficiency. Single-cell analysis localized signature genes to T lymphocyte and myeloid compartments and linked elevated CIPS activity to augmented intercellular communication in platinum-resistant tumors. CIPS captures a CD8+ T cell activation program that powerfully stratifies late-stage HGSOC, forecasts therapeutic benefit and offers a practicable biomarker for personalized immuno-oncology strategies.

The aberrant accumulation of intracellular disulfides promotes cancer cell disulfidptosis; however, how disulfide stress influences tumour-infiltrating CD8+ T cell function remains unknown. Here we demonstrate that lactate dehydrogenase B (LDHB) facilitates intratumoural CD8+ T cell disulfidptosis and exhaustion, leading to impaired antitumour immunity. SLC7A11-mediated cystine uptake by CD8+ T cells induces disulfidptosis, which plays critical roles in the development of exhausted CD8+ T cells. LDHB restricts glucose-6-phosphate dehydrogenase (G6PD) activity in exhausted CD8+ T cells by interacting with G6PD, causing NADPH depletion and consequently triggering disulfidptosis. Accordingly, the loss of LDHB in T cells prevents disulfidptosis-dependent CD8+ T cell exhaustion and improves antitumour immunity. Mechanistically, STAT3 directs LDHB expression to limit G6PD activity and mediate disulfidptosis in exhausted CD8+ T cells. Our results highlight the distinct roles of disulfidptosis and ferroptosis in driving CD8+ T cell exhaustion and suggest a potential therapeutic strategy to target LDHB in cancer immunotherapy.

BACKGROUND:Deep vein thrombosis (DVT) is a prevalent peripheral vascular disorder associated with abnormal epigenetic processes and altered gene expression in endothelial cells. Accumulating evidence has demonstrated that NAT10 (N-acetyltransferase 10)-mediated N4-acetylcytidine modification exerts unique roles in ferroptosis, but its roles are still elusive in DVT. METHODS:To explore the potential mechanism of NAT10 and ferroptosis on thrombogenesis, we used NAT10 and GPX4 (glutathione peroxidase 4) knockout mice as an in vivo model, and utilized techniques, such as RNA immunoprecipitation, acRIP-qPCR (acetylated RNA immunoprecipitation-quantitative PCR), N4-acetylcytidine Dot Blotting assay, and Western blotting, for detailed molecular analysis. RESULTS:GPX4 is a pivotal gene that suppresses ferroptosis. Utilizing endothelial cell-specific GPX4 conditional knockout mice (GPX4fl/flCdh5-Cre+), we proved that ferroptosis in endothelial cells promotes the formation of thrombosis. Previous evidence indicates that NAT10 overexpression induces ferroptosis and downregulates GPX4 expression. Here, we found that NAT10 expression was elevated in DVT mice, and silencing of NAT10 markedly attenuated ferroptosis both in vitro and in vivo. Furthermore, endothelial cell-specific knockout of NAT10 (NAT10fl/flCdh5-Cre+) demonstrated a reduction in endothelial ferroptosis, thereby inhibiting both the formation and progression of DVT. Mechanistic studies indicated that NAT10 facilitated the N4-acetylcytidine modification of HMOX1 (heme oxygenase 1), which enhanced its mRNA stability, leading to the accumulation of ferrous ions, and exacerbating endothelial dysfunction in DVT. CONCLUSIONS:Collectively, our data elucidate that downregulation of NAT10 mitigates endothelial ferroptosis and prevents DVT formation and progression by modulating HMOX1 expression, which offers a potential novel strategy for the prevention and treatment of thrombosis in DVT.

Naphthalene diimides (NDIs) have emerged as key candidates in the realms of photocatalysis and photovoltaics because of their semiconducting properties. However, their potential application in photoelectrochemical (PEC) sensing has yet to be fully explored. In this study, two novel NDI derivatives: 2,2 '-(1,3,6,8-tetraoxo-1,3,6,8-tet- rahydrobenzo[lmn][3,8]phenanthroline-2,7-diyl)dipropionic acid (NDI-COOH) and its bromine-substituted counterpart, 2,2 '-(4,9-dibromo-1,3,6,8-tetraoxo-1,3,6,8-tetrahydrobenzo[lmn][3,8]phenanthroline-2,7-diyl) dipropionic acid (Br-NDI-COOH) were synthesized and characterized. Theoretical and experimental analyses demonstrated that the bromine substitution significantly enhanced the PEC performance of Br-NDI-COOH by extending its absorption spectrum toward visible light. Furthermore, the integration of gold nanoparticles (AuNPs) with Br-NDI-COOH leads to the formation of an AuNPs/Br-NDI-COOH composite material that significantly enhances the PEC signal, which could be used as a signal probe in PEC immunosensor for the detection of the key biomarker carcinoembryonic antigen (CEA). The constructed sensor exhibits remarkable sensitivity, with a detection limit of 1.22 fg center dot mL-1 and a linear response ranging from 10 fg center dot mL-1 to 100 ng center dot mL-1, which indicate the promising potential of the AuNPs/Br-NDI-COOH platform for the sensitive detection of biomarkers in complex biological matrices. This work pioneered the use of NDIs in PEC immunosensing and highlighted the pivotal role of functional group engineering in optimizing the PEC properties of organic semiconductors.