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This study examined the concordance of associations of single nucleotide polymorphisms (SNPs) for acute coronary artery disease (CAD) discovered in Europeans with acute CAD, chronic ischaemic heart disease (IHD) or stroke in Chinese adults. In a nested case-control study of acute CAD (4748 cases/66,227 controls) in China Kadoorie Biobank (CKB), we compared associations of 224 SNPs for acute CAD discovered in Europeans in CARDIOGRAMplusC4D (CC4D) with acute CAD in Chinese. We compared associations of a genetic score (GS-CAD) for 224 SNPs for acute CAD with chronic IHD (n=9000), heart failure (n=1229), stroke (n=10,208) and CVD risk factors (n=70,364) and plasma proteomics (n=3904) in CKB. The strength of associations of 224 CAD SNPs discovered in Europeans was moderately correlated with those for acute CAD in Chinese (r=0.53), but significant associations were only replicated (p<0.05) for 25 SNPs. The strength of associations with acute CAD for a 1 SD higher genetic score for acute CAD in Chinese were 3-fold greater than for chronic IHD or heart failure (1.22 [1.18-1.26] vs 1.07 [1.05-1.10] vs 1.06 [1.00-1.12], respectively) and 7-fold greater than for stroke (1.03; 1.01-1.05). Higher levels of GS-CAD were strongly associated with LDL-cholesterol (LDL-C), moderately with systolic blood pressure (SBP) and weakly with body mass index (BMI), but not with proteomics. The findings demonstrate a moderate concordance of genetic determinants for acute CAD between Europeans and Chinese that were specific for CAD and only weakly associated with chronic IHD, heart failure or ischaemic stroke.

Bacteriophages (phages) are being explored as alternatives or complements to antibiotics because of their ability to selectively kill bacterial pathogens. However, phages that infect many oral bacteria remain undiscovered. Here, we discovered that dental wastewater harbors previously underexplored phage diversity. Viral particles concentrated from dental wastewater displayed diverse morphologies, including abundant filamentous phage-like particles. Deep long-read metagenomic sequencing of concentrated viral particles generated 7.4 billion bases of sequence data and yielded 255 medium- to high-quality viral operational taxonomic units (vOTUs), including 46 predicted complete genomes. Comparison with large phage databases revealed that 63 of these 255 vOTUs had no detectable match, indicating that extensive sequencing of dental wastewater substantially expands the number of potential bacteriophages associated with the human oral microbiome. Host prediction linked many vOTUs to oral-associated bacterial taxa, including species with few or no previously reported phages, such as Porphyromonas gingivalis, Tannerella forsythia, and Candidatus Saccharibacteria. Functional annotation identified diverse genes associated with antiphage defense systems within a subset of vOTUs, suggesting that oral phages may contribute to the movement of genes encoding bacterial immune functions within the oral microbiome. Together, these findings expand the known oral phageome and show that dental wastewater contains a largely untapped diversity of phages.IMPORTANCEThe human oral cavity contains a diverse microbial community, but the bacteriophages (phages) that infect many oral bacteria remain poorly characterized. This gap limits our understanding of how phages shape oral microbial communities. Here, we show that dental wastewater is an underexplored source of oral phage diversity. Deep long-read metagenomic sequencing revealed 255 medium- to high-quality phage operational taxonomic units, many of which are not present in existing oral phage databases. These genomes include predicted phages of periodontal disease-associated bacteria and other oral taxa with few or no known phages. Dental wastewater therefore expands the known human oral phageome and reveals candidate phages linked to bacteria associated with oral health and disease.

Vitamin K was discovered during the 1930s when a strange haemorrhagic disorder was observed in chickens fed a cholesterol-free diet. A fat-soluble agent, present in green leafy vegetables and hog liver, was able to restore haemostasis in the chickens. The chemical structure and the physiological role of vitamin K were uncovered resulting in the Nobel Prize being awarded to Henrik Dam and Edward Doisy in 1943. The discovery of vitamin K led to a breakthrough in our understanding of the human coagulation system, where vitamin K plays a pivotal role in activating prothrombin and other coagulation factors. The prevention of vitamin K-dependent bleeding in newborns by vitamin K prophylaxis was introduced in the 1940s and is today a strong recommendation by the World Health Organization. Vitamin K also became crucial to the management of diseases with high risk of vitamin K deficiency due to malabsorption of fat. Later a new type of drug was developed, vitamin K antagonists, counteracting the physiologic effects of vitamin K for the prevention of thrombotic events. Recent research has indicated that vitamin K may have important functions beyond coagulation in extra-hepatic tissues by promoting healthy bone mineralization and preventing vascular calcification. Vitamin K was first discovered in the 1930s when scientists noticed bleeding problems in chickens lacking it. This breakthrough revealed its key role in blood clotting and led to life&#x2010;saving practices like giving newborns vitamin K to prevent bleeding. It also became essential for treating people with fat absorption issues and for developing drugs that reduce clotting risks. Today, research shows vitamin K may do more than help blood clot&#x2014;it could support strong bones and protect blood vessels from harmful calcium buildup, making it important for overall health.

Distributed arrays of wireless neural interfacing chips with 1-2 channels each, known as "neural dust," could enhance brain machine interfaces (BMIs) by removing wired connections through the scalp and increasing biocompatibility with their submillimeter size. Although several neural dust designs have emerged, currently reported procedures for implanting them in batches place the chips directly inside the brain, which can damage or displace large numbers of neurons. Therefore, a procedure for safely implanting neural dust in batches such that only ultrasmall microwire elements enter the brain is needed. Here, we demonstrate the feasibility of implanting batches of wireless motes that rest on the cortical surface and reach 1 mm brain depths via penetrating carbon fiber electrodes (6.8-8.4 &#x3bc;m diameter) without employing disruptive insertion shuttles. To simulate their implantation, we assembled over 230 mechanically-equivalent carbon fiber motes and affixed them to insertion tools with polyethylene glycol (PEG), a quickly dissolvable and biocompatible material. Then, we implanted batches into rat cortex in vivo and evaluated insertion success and their arrangement on the brain surface. When positioning motes for insertion, we discovered that they readily aggregated in molten PEG such that average array pitches were 5% longer than an individual mote's dimensions (240 &#xd7; 240 &#x3bc;m). Overall, 187/214 (87%) motes tightly-packed in 4 &#xd7; 4 (N = 4) and 5 &#xd7; 5 (N = 6) square grid configurations successfully inserted into rat cortex. After implantation, measurements of how much motes tilted (22 &#xb1; 9&#xb0;, X&#x304; &#xb1; S) and had been displaced from their original positions were smaller than those measured in the literature for devices implanted inside the brain. Collectively, these data establish the mechanical viability of assembling and safely implanting motes with ultrasmall electrodes and epicortically-situated chips, motivating the use of arrays with similar geometries in future BMIs.

Bevacizumab is widely used as an anti-angiogenic maintenance therapy in ovarian cancer; however, there are currently no validated clinical criteria to guide patient selection for its use. To satisfy the urgent need for bevacizumab response biomarkers, we created a novel RNA-seq dataset (n&#x2009;=&#x2009;244) and applied unsupervised and supervised machine learning to identify expression signatures associated with benefit from adding bevacizumab to standard treatment and validated our findings using a previously published microarray dataset (n&#x2009;=&#x2009;377). Additionally, we validated the existence of the discovered signatures using RNA-seq data from the TCGA-OV cohort (n&#x2009;=&#x2009;426) and performed public expression data mining to provide a biological interpretation of the prioritized signature. Among expression signatures reproducibly detected in independent datasets, one was prioritized as a potential predictive biomarker for bevacizumab benefit. Further stratified analysis revealed that over-expression of this signature was associated with improved overall survival in patients who received bevacizumab in addition to standard chemotherapy in both novel (HR&#x2009;=&#x2009;0.41, 95% CI: (0.23-0.74), adj.p-value&#x2009;=&#x2009;0.008) and previously published cohorts (HR&#x2009;=&#x2009;0.51, 95% CI: (0.34-0.75), adj.p-value&#x2009;=&#x2009;0.003), while no significant survival benefit from bevacizumab was observed in patients negative for this signature. We hypothesize that this signature may be associated with stemness-like features, possibly driven by CTCFL. In addition, we identified several other signatures reproducible in independent datasets and not related to known molecular subtypes of ovarian cancer, which may also represent biomarker candidates and require further validation in additional RNA-seq data. We identified a previously undescribed expression signature with potential predictive value for bevacizumab benefit, and revealed transcriptional heterogeneity of ovarian cancer that extends beyond current molecular classifications. Given the high heterogeneity of ovarian cancer and that the novel signature only partially explains variation in survival outcomes under bevacizumab treatment, larger RNA-seq datasets are required to further improve predictive models.

Ticks are important vectors of emerging viruses, and China's ecological landscapes may influence the transmission dynamics of tick-borne viruses (TBV). In 2021, a total of 2867 ticks collected from Inner Mongolia, Hebei, Hunan, and Hainan provinces were subjected to metagenomic sequencing to characterize TBV diversity. A total of eleven TBVs were identified, comprising three members of the family Phenuiviridae (severe fever with thrombocytopenia syndrome virus, Lihan tick virus, Dabieshan tick virus), three belonging to Nairoviridae (Huangpi tick virus 1, Shanxi tick virus 2, Henan tick virus), one in Chuviridae (Wuhan tick virus 2), one in Rhabdoviridaes (Wuhan tick virus 1), and three unclassified viruses (Hubei tick virus 2, Bole tick virus 4, and Tacheng tick virus 7). Viral composition varied significantly across tick species and geographic regions, with phylogenetic analysis revealing distinct regional clustering patterns. Notably, Lihan tick virus was detected for the first time in Hunan Province, Bole tick virus 4 was identified in argasid ticks from Inner Mongolia for the first time, and a novel lineage of severe fever with thrombocytopenia syndrome virus was discovered in Shijiazhuang, Hubei Province. These findings underscore substantial TBV diversity shaped by tick species and geographic origin, emphasizing the necessity for ongoing surveillance to guide the development of targeted prevention and control strategies.

Leukocyte cell-derived chemotaxin 2 (LECT2), a newly discovered hepatokine involved in immunomodulation and inflammatory processes, has recently been implicated in diabetic retinopathy pathogenesis. However, the specific role and mechanism of LECT2 in diabetic retinopathy remain largely unclear. A publicly available liquid biopsy proteomics dataset was reanalysed and validated using retinal samples from individuals with diabetic retinopathy. A LECT2-knockdown (Lect2+/-) mouse model of diabetic retinopathy was established to evaluate the role of LECT2 in vivo. Retinal pathology was assessed by Periodic Acid-Schiff staining and H&E staining, and LECT2 expression was assessed by western blotting. In parallel, a high glucose (HG)-induced human M&#xfc;ller cell model was used to investigate the subcellular localisation and functional effects of LECT2. LECT2 expression and inflammatory signalling were analysed following LECT2 knockdown or overexpression, and its nucleus-cytoplasm distribution was examined by fractionation assays. The interaction between LECT2 and ribosomal protein S27a (RPS27A) was characterised by immunoprecipitation-MS, co-immunoprecipitation, molecular docking and split-GFP assays, followed by RPS27A silencing to assess its effects on inflammatory protein expression. Proteomic reanalysis of proliferative diabetic retinopathy liquid biopsy data identified 1479 upregulated proteins, with chemotaxis among the most significantly enriched Gene Ontology terms (false discovery rate <0.001). Among 17 chemotaxis-related candidate proteins, LECT2 emerged as a potential regulator of diabetes-associated inflammation, a finding further supported by its elevated expression in the retinas of individuals with diabetic retinopathy. In diabetic Lect2+/- mice, LECT2 deficiency aggravated retinal microvascular injury and inflammatory responses. LECT2 was predominantly expressed in retinal M&#xfc;ller cells, implicating it in glia-associated retinal inflammation. In HG-treated human retinal M&#xfc;ller cells, RPS27A was identified as a downstream target of LECT2 and was upregulated under hyperglycaemic conditions. Mechanistically, HG stimulation increased the expression and nuclear accumulation of both LECT2 and RPS27A. LECT2 interacted with RPS27A at the Lys48 site, promoting its nuclear retention and limiting its cytoplasmic translocation. This, in turn, inhibited I&#x3ba;B&#x3b1; ubiquitination and degradation, thereby suppressing NF-&#x3ba;B-driven inflammatory signalling. Taken together, our studies indicated the protective role of LECT2 in diabetes-induced dysfunction of retinal M&#xfc;ller cells, supporting the feasibility of targeting LECT2 in the management of diabetic inflammation and microvasculopathy.

Mitochondrial dysfunction is increasingly implicated in schizophrenia (SZ) pathogenesis. To maintain mitochondrial homeostasis under cellular stress, a sophisticated mitochondrial quality control (MQC) mechanism has developed, encompassing mitochondrial biogenesis, dynamics, and mitophagy. This study systematically evaluated MQC in peripheral leukocytes of 42 SZ patients and 43 healthy controls through morphological analysis, MQC gene expressions, mitochondrial DNA (mtDNA) maintenance, and oxidative damage. Besides, we validated the regulatory effects of oxidative stress on MQC in vitro using a neuronal model treated with hydrogen peroxide. We observed mitochondrial fragmentation in SZ, characterized by increased organelle numbers with reduced sizes. This was supported by imbalanced MQC, with expression of biogenesis-related genes SIRT1 and TFAM upregulated (P&#x2009;=&#x2009;.008 and 0.027, respectively), and mitophagy receptor gene PHB2 suppressed (P&#x2009;=&#x2009;.041), indicating enhanced biogenesis but impaired mitophagy. Despite enhanced biogenesis, mtDNA copy number was lower (P&#x2009;<&#x2009;.001) with more oxidative damage (P&#x2009;=&#x2009;.037). Furthermore, we discovered deficits in antioxidant capacity, including reduced coenzyme Q10 levels and superoxide dismutase (SOD) activity, with SOD decline correlating with mtDNA depletion. This suggests redox imbalance contributes to MQC dysregulation, supported by findings from an oxidation-damaged neuronal model. Moreover, disrupted MQC functionally impaired energy metabolism, reflected by downregulated NDUFV1 expression (P&#x2009;=&#x2009;.031) and increased lactate-to-pyruvate ratios (P&#x2009;<&#x2009;.001). Our findings demonstrated MQC imbalance in SZ, manifested as mitochondrial fragmentation and mtDNA depletion, probably resulted from oxidative damage. These disruptions may underlie the energy metabolism abnormalities in SZ.

To ensure effective development and assessment of detection dogs, Auburn University Canine Performance Sciences program has implemented a structured behavioral evaluation at four developmental milestones. At each timepoint, trainers scored candidate detection dogs on 11 subtests evaluating detection performance and environmental soundness using behavioral component (BC) scores. Additionally, trainers rated each dog's overall suitability for operational detection work using a singular global score. To investigate the relative importance of different metrics in predicting final outcomes, we leveraged a longitudinal dataset collected from 304 dogs. Using a machine learning classifier, we discovered that suitability (S) scores at 12-months of age were highly predictive of training outcomes, achieving a prediction accuracy of 74.3%. The S scores appear to reflect a synthesis of subtest scores across relevant behavioral domains, illustrated by their correlative structures. To determine if S scores could be replicated using only BC scores, we estimated computationally synthesized suitability (CSS) scores at each timepoint using five significant BC scores as predictors in a linear model. Strong correlations were observed between trainer-reported suitability and CSS, with spearman's correlation coefficients exceeding 0.84 at all timepoints, demonstrating CSS scores' excellent ability to predict suitability. As predictors of training outcome, trainer-reported S scores demonstrated high accuracy, while CSS scores exhibited high precision (76.7%). Notably, both suitability metrics increase over time in dogs deemed operationally capable but not in unsuccessful dogs. Our findings provide novel insights into the importance of data-driven approaches by combining expert trainer global assessments of suitability and BC scores with computational modeling in detection dog development.

Gossypiboma, also known as a retained surgical sponge, is a rare but preventable postoperative complication that results from the inadvertent retention of textile surgical materials within the body. Post-prostatectomy gossypiboma is exceedingly uncommon and poses diagnostic challenges due to its nonspecific and delayed clinical presentation. This case highlights a rare intraprostatic gossypiboma discovered incidentally during transurethral prostate surgery, underscoring the importance of meticulous surgical counts and long-term vigilance in postoperative patients. We report the case of a 73-year-old male with progressive lower urinary tract symptoms of 3&#xa0;years' duration, who had undergone an open prostatectomy for presumed benign prostatic hyperplasia 1 year earlier. During transurethral resection of the prostate for persistent bladder outlet obstruction, a retained surgical gauze embedded within the prostatic bed was unexpectedly identified, associated with purulent material. Endoscopic removal was unsuccessful, necessitating conversion to an open suprapubic approach for complete extraction. The patient had an uneventful postoperative recovery following appropriate surgical and antibiotic management. Gossypiboma remains underreported due to medicolegal concerns, yet it represents a significant source of postoperative morbidity. Risk factors include emergency surgery, hemorrhagic operative fields, inadequate sponge counts, and changes in operative plans. In urologic surgery, retained sponges are particularly rare and may masquerade as infection, malignancy, or recurrent obstruction. This case illustrates an unusual intraprostatic location, delayed presentation, and diagnostic difficulty, emphasizing the need for heightened suspicion in patients with persistent or unexplained postoperative symptoms. This study provides several learning points, such as post-prostatectomy gossypiboma should be considered in patients presenting with unexplained persistent lower urinary tract symptoms after prostate surgery. Symptoms are vague, and intraoperative diagnosis remains common. High diagnostic suspicion and conversion to open prostatectomy, if we fail to remove the foreign body with the resectoscope, are the mainstays of treatment.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an essential cytosolic DNA-sensing system that plays an important role in the regulation of innate immune and inflammatory responses in the central nervous system (CNS). It was first discovered as a promising antiviral defense cascade and has since been shown to execute broader functions in neuroinflammation and neurodegeneration. The pathway can become hyperactive with the release of endogenous DNA from damaged nuclei, mitochondria, or genomic instability, leading to chronic production of type I interferon (TI-IFN), various pro-inflammatory cytokines, and eventually contributing to chronic neuroinflammatory diseases. Recent studies have found that dysregulated cGAS-STING signaling is associated with several neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), stroke, and age-related neurodegeneration. In the CNS, chronic activation of this pathway leads to activation of microglia, oxidative stress, breakdown of the blood-brain barrier (BBB), impaired function of the synapses, and neuronal death. Mitochondrial dysfunction and cytosolic release of mitochondrial DNA (mtDNA) further promote inflammatory signaling, thus perpetuating neurodegeneration. This review highlights the molecular and pathological mechanisms of cGAS-STING signaling in a broader aspect of neurological disorders and appraises the novel therapeutics already under development to inhibit this pathway to regulate neuroinflammation and enhance neurological outcomes.

Oncolytic viruses (OVs) is a class of promising cancer biotherapeutics by selectively lysing tumor cells and stimulating antitumor immunity. However, most OV-based clinical efficacy were often restricted by rapid viral clearance mediated by pre-existing neutralizing antibodies and immunosuppressive tumor microenvironment (TME). These barriers particularly limit the efficient activation of T cell-mediated immune responses, thereby compromising durable systemic antitumor effects. Leveraging the distinctive advantage that oncolytic parapoxvirus ovis (ORFV) does not induce neutralizing antibodies in vivo, we developed an engineered ORFV recombinant through simultaneous deleting multiple virulence-associated genes together with inserting Il15 gene, named ORFV&#x394;-IL15. This newly generated ORFV recombinant retains full replication competence and significantly potentiating anti-tumor efficacy, which was demonstrated by greater capacity in suppressing tumor growth and metastasis especially in immunologically 'cold' tumors. Mechanistically, ORFV&#x394;-IL15 reprograms TME by modulating inflammatory cytokines, affecting intratumoral T cell recruitment and redirecting T cell subpopulation distribution. Functionally, ORFV&#x394;-IL15 could induce T cell involved co-stimulation, tumor antigen presenting and tumor killing, which was illustrated by the finding that antigen-specific, cytotoxic and activated CD8+ T cells were highly enriched in tumor lesions. Notably, systemic antitumor immunity was induced, as abscopal effects against distant untreated tumors have been discovered, indicating that long-term immunological memory has been established. Our findings establish ORFV&#x394;-IL15 as a novel therapeutic agent that integrates oncolytic and immunoregulatory functions, demonstrating robust tumor-suppressive efficacy and offering a promising strategy for next-generation oncolytic virus engineering.

Fusarium head blight (FHB) is a devastating disease that severely impacts global wheat (Triticum aestivum L.) production. Sumai 3, a wheat cultivar widely used in breeding programs for its strong FHB resistance, has not been fully resolved at the chromosome level. Here, we present a high-quality chromosome-scale assembly of Sumai 3 using PacBio HiFi reads and chromosome conformation capture sequencing. The 14.6 Gb assembly consists of 832 contigs, with the longest contig being 245.2 Mb and a contig N50 of 41.90 Mb, which were scaffolded into 21 pseudomolecules. De novo annotation identified 104,620 high-confidence protein-coding genes and found 92.67% of the genome to consist of repetitive sequences. Synteny analysis showed strong collinearity between Sumai 3 and the wheat reference sequence Chinese Spring IWGSC RefSeq v2.1 (CS). Structural variant analysis identified chromosome 2A with the highest number of deletions (2773) and insertions (2645), while chromosome 3B had the most inversions (359). Duplications were most frequent on 2A (337), and contractions on 5B (122). The gene content of the major resistance quantitative trait loci on 3B, Fhb1, largely validates previous annotations for CS, although we discovered two new genes at approximately 12.4 Mb, including an additional copy of a terpene synthase, further suggesting homology with CS 3D over 3B. Differential expression analysis highlighted up-regulation of three genes coding pore-forming toxin-like protein, sina superfamily protein, and plastid-lipid-associated proteins potentially involved in FHB resistance. This assembly provides critical insights into FHB resistance and offers a valuable genomic resource for wheat breeding programs. Fusarium head blight is a destructive disease of small grains that decreases yield and grain quality, leading to reduced revenue for producers. The most efficient method of limiting disease in the field is cultivation of genetically resistant crop varieties, which are developed through deployment of resistance gene regions. Several of these gene regions arise from the remarkably resistant variety Sumai 3, which has been the most important source for small grains breeders throughout the world. Here we present a high&#x2010;quality genome sequence of this variety along with a characterization of all its genes. This information will provide an accurate framework to accelerate research into the molecular mechanism of how this variety combats disease and make it easier to utilize these gene regions in the future.

Killer plasmids are cytosolic linear dsDNA plasmids found in many species of Saccharomycotina, the budding yeasts. They encode toxins that give their hosts an advantage against competitor yeasts in the environment. They cause cell death in their prey by targeting non-coding RNAs of the translation apparatus, either tRNAs or rRNAs. We recently discovered that similar toxin systems are integrated into the nuclear genomes of many filamentous ascomycetes. Cytosolic linear plasmids similar to killer plasmids are also present in two deeply divergent phyla of terrestrial fungi (Zoopagomycota and Mucoromycota), although they have not yet been shown to have killing activity. It is becoming apparent that plasmid-encoded toxin systems or toxin-like systems are far more widespread than previously considered and have impacted upon fungal biology and evolution for hundreds of millions of years.

Estimating age at death is an essential part of identification when a body is discovered in the skeletal state. Several methods have been developed using the pubic bone in particular. The Suchey-Brooks method is the best known and most widely used. The more recent Berg and Hartnett methods have shown increased accuracy although they have not been widely tested.The aim of this study is to compare the Suchey-Brooks, Berg and Hartnett methods applicable to the pubic bones, to provide practical guidance to use these methods. For this study, we used a French collection of mature forensic contemporary pubic bones. We included skeletal specimens from 67 females and 221 males over the age of 20. The evaluators successively and independently applied the Suchey-Brooks, Berg and Hartnett methods to each left pubic bone. The Berg method reduced inaccuracy in females over 70 (12.5 vs. 22.2 years for Suchey-Brooks), while the Hartnett method showed improved performance in males over 60. Intra-observer agreement was almost perfect for the three methods, and inter-observer agreement was moderate or good depending on the method used and the sex. The Berg and Hartnett methods were the most precise for estimating the age at death of older individuals. Using them in addition to the Suchey-Brooks method beyond phase V or VI would enable a better age at death estimation, provided there is no taphonomic degradation of the bone.

Although FMS-like tyrosine kinase-3 (FLT3) inhibitors initially induce a favorable response in AML patients, their long-term efficacy is often limited by the development of resistance. Bone marrow stromal cells (BMSCs), a key component of AML bone marrow niche, support leukemia cell survival and drive drug resistance through multiple approaches like direct contact, cytokine secretion, and exosome release. BMSC-mediated AML resistance involves complex and heterogeneous mechanisms that vary depending on the drug type and the characteristics of the leukemic cells. Therefore, this study seeks to elucidate how BMSCs interact with FLT3-ITD-mutated AML cells to confer FLT3 inhibitor resistance, aiming to identifying potential therapeutic targets to overcome such resistance. We discovered that BMSCs co-cultured with leukemia cells exhibited elevated expression of COX-2 and its product PGE2. BMSC-derived PGE2 suppressed ferroptosis in AML cells by modulating fatty acid metabolism and enhancing the glutathione antioxidant system. Additionally, PGE2 activated the GSK3&#x3b2;/&#x3b2;-catenin signaling pathway, facilitating the nuclear translocation of &#x3b2;-catenin, which influenced the apoptotic rates of AML cells. Proinflammatory cytokines such as TNF-&#x3b1; and IL-1&#x3b2; secreted by FLT3-ITD-mutated AML cells suppressed NR2F2 expression in BMSCs, leading to de-repression of COX-2 and subsequent PGE2 secretion, further amplifying this regulatory loop. Taken together, our findings reveal a novel mechanism whereby the NR2F2/COX-2/PGE2 axis modulates the sensitivity of AML cells to FLT3 inhibitors, and targeting this circuit may serve as an adjuvant therapy to improve FLT3 inhibitor efficacy.

Lung cancer ranks among the most prevalent malignancies globally. Despite progress in early detection and standard therapies lowering overall mortality, there remains an urgent demand for optimized combinatorial regimens, reliable biomarkers and individualized strategies to advance precision lung cancer care. Epigenetic-targeted agents, represented by DNA methylation and histone lysine deacetylase (HDAC) inhibitors, have exhibited encouraging anti-tumor effects, and the Food and Drug Administration (FDA)-approved EZH2 inhibitor tazemetostat has further validated the translational value of epigenetic therapy across multiple tumors. This narrative review systematically summarizes epigenetic alterations and corresponding targeted inhibitors in lung cancer, and clarifies the clinical prospects of epigenetic tools for diagnostic biomarker development and stratified precision treatment. We searched PubMed and Web of Science Core Collection from database inception to January 31, 2026 with keywords covering lung cancer, DNA methylation, histone modification and epigenetic targeted therapy. Only full-text English original articles and reviews were retained. This review systematically characterizes aberrant epigenetic signatures in lung cancer, encompassing DNA methylation, histone methylation, and the recently discovered histone lactylation, while detailing epigenetic biomarkers applicable to diagnosis and targeted therapy. We further summarize subtype-specific research advances of KMT/KDM, HDAC, EZH2 and LSD1 inhibitors in distinct lung cancer subtypes, with core functions including suppressing tumor proliferation, modulating neuroendocrine phenotypic transition, reversing therapeutic resistance, and amplifying anti-tumor immune responses. Dysregulated epigenetic modifications serve as core drivers of lung cancer progression, and various epigenetic small-molecule inhibitors possess broad application potential for lung cancer precision treatment. Combined regimens integrating epigenetic agents with immunotherapy or chemotherapy can strengthen anti-tumor responses, yet subtype heterogeneity and unsatisfactory clinical efficacy of some targeted drugs remain major obstacles. The accumulated preclinical and clinical epigenetic evidence summarized herein provides solid theoretical support for developing novel diagnostic biomarkers and individualized stratified therapeutic strategies against lung cancer.