Background:Pericarotid fat density (PFD) obtained by computed tomography angiography (CTA) could serve as a surrogate biomarker reflecting local inflammation. The study aimed to quantitatively estimate the impact of PFD on cognitive and functional outcomes in patients with cerebral small vessel disease (CSVD). Methods:A total of 71 symptomatic and 55 asymptomatic CSVD patients were prospectively recruited. Imaging characteristics comprising CSVD markers and carotid artery markers (PFD values, calcification, stenosis degree, ulceration, and maximum wall thickness) were analyzed. Cognitive assessments were performed 90 days after acute infarcts, including diverse neuropsychological scales (the Montreal Cognitive Assessment, the Shape Trail Test, the Stroop test, and the Rey-Osterrieth Complex Figure Test) and sensitive event-related potential (ERP) detection. Worse functional outcomes were defined as a Modified Rankin Scale change score (ΔmRS) ≥ 0 (ΔmRS = mRS90-day-mRSbaseline) in the symptomatic CSVD cohort. Results:Symptomatic CSVD showed significantly higher PFD values than asymptomatic CSVD. As indicated by multiple scales and P3a/P3b amplitude, cognitive function in symptomatic CSVD was poorer than that in asymptomatic CSVD. Symptomatic CSVD showed numerically stronger correlations between PFD values and cognitive impairment, with more parameters involved and the strongest correlations existing among ERP data. Maximum PFD was identified as an independent predictor of adverse functional outcomes (p < 0.001), and a predictive model incorporating maximum PFD showed better performance (AUC = 0.939). Conclusion:The increased PFD values were closely associated with cognitive impairment and adverse functional outcomes in CSVD patients, especially among those with symptoms. Our findings could assist in the risk stratification and tailored treatment of CSVD patients to facilitate prognosis.

Ménière's disease (MD), a chronic inflammatory disorder with age-related increased incidence, exhibits poorly understood pathogenesis and limited therapeutic options. Here, we demonstrate that cellular senescence, marked by mitochondrial damage, reactive oxygen species accumulation, and senescence-associated secretory phenotype (SASP), is prevalent in the vestibular tissue of MD patients and an endolymphatic hydrops mouse model. The transcription factor GATA4 is upregulated in MD and mice, and its genetic deletion in hair cells alleviates LPS-induced audio-vestibular dysfunction and cellular senescence in mice and HEI-OC1 cells. Mechanistically, HDAC6 interacts with GATA4 and restrains its nuclear transport, while RNA-seq and ChIP-seq identify HtrA1, a serine protease, as a direct transcriptional target of GATA4. Inhibition of HDAC6 or AAV-mediated HtrA1 overexpression exacerbates MD-like symptoms, whereas inhibition of HtrA1 by Galegenimab ameliorates these phenotypes in mice. In aged mice, GATA4 deletion reduces age-related audio-vestibular deficits and senescence markers. Collectively, our findings establish GATA4 as a critical regulator of cellular senescence and inflammaging in inner ear pathologies, providing promising therapeutic targets for MD and age-related audio-vestibular disorders.

BACKGROUND: Approximately 30% of patients taking metformin experience gastrointestinal adverse events, with 5%–10% discontinuing the drug due to intolerance. The aim of our study is to develop and externally validate a prediction model for metformin intolerance in elderly patients with type 2 diabetes. METHODS: This study utilized data from three independent cohorts of Chinese elderly metformin-naïve patients with type 2 diabetes. The derivation cohort consisted of 538 patients. External validation was performed using data from a separate cohort of 319 patients. Intolerance was assessed after patients initiated metformin and maintained treatment for over four weeks. Patients who were unable to complete at least four weeks of treatment due to gastrointestinal adverse effects were also classified as intolerance. RESULTS: In the derivation cohort, the median age was 67 years, median HbA1c was 8.1%, and 45% were female. The external validation cohort had a median age of 70 years, median HbA1c of 7.6%, and 54.5% were female. Metformin intolerance occurred in 75 patients (13.9%) in the derivation cohort and 63 patients (19.7%) in the external validation cohort. Multivariable analysis identified ten variables: gender, age, body mass index, fasting glucose, HbA1c, aspartate aminotransferase, gamma-glutamyl transferase, antidepressants, proton pump inhibitors and clopidogrel. In the derivation cohort, the model demonstrated an AUC of 0.889, with a sensitivity of 0.813 and a specificity of 0.773. Upon external validation, the model maintained good discriminative ability with an AUC of 0.883. CONCLUSIONS: We developed and validated a multivariable prediction model for metformin intolerance in Chinese elderly patients. This model may help physicians to be more confident when prescribing metformin, and reduce the intolerance of metformin. CLINICAL TRIAL NUMBER: Not applicable.

BackgroundTo investigate whether Fcγ receptors (FcγRs) expression on peripheral blood monocytes predicts clinical response to etanercept in rheumatoid arthritis (RA).MethodsIn this prospective cohort study, FcγRs expression on peripheral blood monocyte subsets was analyzed by flow cytometry. The primary outcome was the change in DAS28-CRP from baseline to week 12. The secondary outcome was the change in DAS28-ESR.ResultsFollowing etanercept therapy, the proportion of FcγRI-positive monocytes and classical (CD14++CD16−) monocytes was reduced, while the proportion of non-classical (CD14+CD16++) monocytes was increased. Changes in intermediate monocytes (CD14++CD16+) were positively correlated with both DAS28-CRP change and DAS28-ESR change at week 24 after etanercept therapy. Patients with high intermediate (CD14++CD16+) monocytes showed significantly greater reductions in DAS28-CRP at week 12.ConclusionIntermediate monocytes (CD14++CD16+) were correlated with improvements in DAS28-CRP achieved by week 12 following etanercept therapy. RA patients with low intermediate monocytes may derive less benefit from etanercept treatment.

Lipid nanoparticles (LNPs) represent a leading non-viral platform for mRNA delivery, yet achieving efficient tissue-specific targeting and cytosolic release remains challenging. This study addresses this issue by engineering the structure of trace PEG-lipids-a minor but critical component of LNPs. A library of 45 novel PEG-lipids was constructed, and Pr-181-277-featuring an asymmetric linker-was identified as a potent enhancer of hepatic mRNA delivery. Replacing the conventional PEG-lipid in standard LNPs with Pr-181-277 led to a 4.5-fold increase in luciferase mRNA expression and a 5.3-fold improvement in Cre-mediated gene editing efficiency in the liver. Mechanistic studies reveal a synergistic two-step mechanism: 1) In vivo, Pr-181-277 drives the formation of a protein corona enriched with albumin, which could explain the observed liver accumulation. 2) Its structure concurrently enhances membrane instability, which facilitates rapid endosomal escape and cargo release. Our work demonstrates that minimal, rational redesign of the PEG-lipid structure can coordinately overcome both extracellular and intracellular barriers, providing a powerful and simple strategy to advance LNP-based therapeutics.

Glucose metabolism disorders (GMDs) are a major global health challenge, characterized by overlapping pathophysiological mechanisms. Emerging research has illuminated a reciprocal association between diabetes mellitus (DM) and neurodegenerative diseases (NDs). Specifically, hyperglycemic states intensify neuroinflammatory cascades, oxidative stress, and aberrant protein misfolding (e.g. amyloid-β aggregation), whereas neurodegenerative diseases (NDs) disrupt systemic glucose homeostasis.Thus, novel antihyperglycemic agents—including sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors—have garnered attention for their multi-target regulatory properties beyond glycemic control, demonstrating potential in mitigating neurodegenerative pathology.Preclinical studies indicate that these agents improve glycemic control and exert neuroprotective effects—including inhibition of neuroinflammation, reduction of Aβ accumulation, and enhancement of synaptic plasticity—primarily in experimental models; however, robust confirmatory data from large‑scale clinical trials in neurodegenerative diseases remain limited.This review systematically explores the multi-target regulatory abilities of novel hypoglycemic agents, including SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors, beyond hypoglycemia.We evaluate the clinical evidence supporting their therapeutic potential in glucose metabolism disorders and related neurodegenerative diseases, while addressing challenges such as unclear molecular pathways and the need for large-scale validation.Based on the existing evidence and limitations, we have proposed the key directions for future research, including clarifying the collaborative mechanism, optimizing the drug delivery system, and developing individualized treatment strategies.

Gouty arthritis (GA) is a recurrent inflammatory joint disease initiated by monosodium urate (MSU) crystal deposition and driven by progressive immune dysregulation. The collapse of immune tolerance, together with persistent synovial inflammation and pathogenic cytokine imbalances, jointly exacerbates joint injury. Here, we design a bioresponsive therapeutic platform composed of regulatory T cell (Treg)-derived exosomes co-loaded with growth arrest-specific protein 6 (Gas6), engineered to preferentially home to inflamed joints via CCR2-guided chemotactic targeting. The two components of the hybrid-Gas6 and Treg exosomes-exert both independent and synergistic immunomodulatory effects. By mitigating inflammation and reprogramming the tissue environment toward a tolerogenic state, the system bridges innate and adaptive immunity to restore overall immune function. In an MSU-induced murine GA model, this therapy not only alleviates key clinical symptoms, but also promotes the expansion of regulatory T cells and suppresses TH17 responses, leading to restoration of a more tolerogenic immune balance. Together, our study presents a cell-free, CCR2-guided immunoengineering approach that achieves targeted delivery and coordinated immune reprogramming, offering a promising strategy for treating GA and other disorders associated with immune imbalance.

BackgroundMethylphenidate is widely prescribed for the clinical management of pediatric patients with attention-deficit/hyperactivity disorder (ADHD), yet its safety profile remains a subject of ongoing concern. This study aims to characterize the real-world safety profile of methylphenidate in children and adolescents using the FDA Adverse Event Reporting System (FAERS) database.MethodsAdverse drug event (ADE) reports for individuals aged 6–17 years were extracted from the FAERS database via OpenVigil 2.1. Disproportionality analyses were performed to detect methylphenidate-associated safety signals, including overall signal detection as well as subgroup analyses stratified by gender and dosage form.ResultsFrom 8,585 reports, methylphenidate-associated adverse drug reaction (ADR) signals involved 16 System Organ Classes (SOCs), most frequently psychiatric disorders; general disorders and administration site conditions; and nervous system disorders. Several potential signals not listed in current drug labels were identified, including abnormal behavior, disturbance in social behavior, and coronary artery dissection. Gender-specific analyses revealed 86 positive signals in males and 90 in females, with 41 male-exclusive and 45 female-exclusive signals. Male-exclusive signals included arrhythmia, coronary artery dissection, and acute myocardial infarction. Female-exclusive signals included tachycardia and application site reactions. Among positive signals detected in both genders, female patients showed higher reporting of application site erythema, agitation, application site pruritus, precocious puberty, and application site discolouration, whereas male patients showed higher reporting of aggression, tics, and growth retardation. Dosage-form-specific analyses showed that the immediate-release formulation was associated with acute, severe signals (e.g., sudden death, syncope). The oral extended-release formulation accounted for the largest number of unique signals (n = 63) in this dataset, although this should be interpreted with caution given differences in reporting volume across formulations. The transdermal patch was predominantly associated with application site reactions (e.g., erythema, pruritus).ConclusionThis study identified overall, gender-, and dosage-form-specific ADR signals for methylphenidate in pediatric patients, including signals not currently listed in drug labels. Distinct ADR signal profiles were observed across gender and dosage-form strata. Individualized pharmacovigilance strategies may be informed by these subgroup-specific ADR signal profiles. These findings contribute to the current understanding of methylphenidate-associated ADE in children and adolescents and warrant further validation in future studies.

Recent studies have found that VDBP gene polymorphism is closely related to the pathogenesis of some respiratory diseases. Rs7041 and rs4588 are two major single-nucleotide polymorphisms(SNPs) in the GC gene encoding VDBP. Different combinations of these variants give rise to three major haplotypic isoforms, GC*1F, GC*1S, and GC*2, which may influence pulmonary immune-inflammatory responses and immune regulation. This systematic review and meta-analysis aimed to clarify the associations between VDBP gene polymorphisms and respiratory diseases including chronic obstructive pulmonary disease(COPD), asthma, Corona Virus Disease-2019(COVID-19) and tuberculosis, so as to provide evidence for the formulation of individualized prevention and therapeutic strategies in the future. We searched the Pubmed, web of science, Wanfang, Embase and China National Knowledge Infrastructure(CNKI) to find the eligible case–control studies. Study quality was assessed using the Newcastle–Ottawa Scale (NOS). Forest plots were generated using Review Manager version 5.4, and pooled odds ratios (ORs) with 95

BackgroundComposite indices integrating inflammation, nutritional reserve, and metabolic status may improve early prognostic assessment after acute ischemic stroke (AIS). This study examined the associations of the C-reactive protein-to-albumin ratio (CAR) and the CRP–triglyceride–glucose index (CTI) with 90-day functional outcomes.MethodsA Korean single-center stroke registry (2010–2016) was analyzed (n = 1,484). CAR and CTI were calculated from admission laboratory tests. The primary endpoint was 90-day unfavorable functional outcome defined as modified Rankin Scale 3–6. Associations were examined using multivariable logistic regression with standardized exposures; restricted cubic splines assessed non-linearity. Prognostic performance was evaluated using receiver operating characteristic analysis and a parsimonious model derived with penalized regression. Internal validation was performed using repeated 10-fold cross-validation, and model calibration was assessed using a calibration plot, calibration intercept, calibration slope, and Brier score.ResultsUnfavorable outcomes occurred in 414 patients (27.9%). After full adjustment, higher CAR (OR 1.25, 95% CI 1.09–1.43) and higher CTI (OR 1.38, 95% CI 1.19–1.60) were independently associated with unfavorable outcome. CTI showed an approximately linear risk gradient, whereas CAR showed evidence of a non-linear association. As single predictors, CAR and CTI yielded AUCs of 0.656 and 0.651 and outperformed albumin, triglycerides, and fasting plasma glucose. A six-variable model including sex, age, body mass index, admission NIHSS, CAR, and CTI achieved an apparent AUC of 0.837. Internal validation showed stable performance, with a mean cross-validated AUC of 0.831, mean Brier score of 0.142, calibration intercept of 0.023, and calibration slope of 1.018.ConclusionCAR and CTI, derived from routine admission laboratory tests, were associated with 90-day functional outcomes after acute ischemic stroke and may aid early prognostic assessment. The derived six-variable model showed acceptable internal performance, but should be considered exploratory pending external validation.

C-type lectins (CTLs) play a crucial role as pattern recognition receptors (PRRs) in the innate immune system. Nevertheless, the underlying mechanisms of CTL-mediated immune recognition and response in bony fish remain poorly understood. In the current study, a CTL member, namely CaCTL4E, was characterized in Cromileptes altivelis, and its biological functions and roles in response to bacterial infection were analyzed. The CaCTL4E gene encodes 254 amino acids with a 765 bp coding sequence and exhibits typical C-type lectin structural features, including a carbohydrate recognition domain (CRD), six conserved cysteine residues, a WIGL motif, and a predicted mannose-binding EPN motif. In healthy C. altivelis, CaCTL4E was differentially expressed in all tested tissues, with a predominant expression in the liver. Notably, upon Vibrio harveyi stimulation, the expression of CaCTL4E in the spleen and head kidney was significantly upregulated, indicating its active involvement in the immune response. The recombinant CaCTL4E (rCaCTL4E) exhibited the ability to agglutinate red blood cells and four bacteria (V. harveyi, Edwardsiella tarda, Streptococcus agalactiae, and Staphylococcus aureus), as well as to bind these bacteria and four pathogen-associated molecular patterns (PAMPs: lipopolysaccharide, peptidoglycan, mannose, and galactose). Interestingly, the binding of rCaCTL4E to PAMPs competitively inhibited its bacterial binding and agglutination activities. Moreover, rCaCTL4E directly inhibited the growth of the four bacteria in vitro. In vivo, the overexpression or knockdown of CaCTL4E led to a decrease or increase in the bacterial burden, respectively. Importantly, rCaCTL4E also exhibited immunomodulatory properties by enhancing the phagocytic activity of head kidney macrophages. These results provide evidence that CaCTL4E acts as the important PRR, and lay a foundation for further understanding the process of CaCTL4E participating in the immune response to pathogenic infections.

Objective:This study aims to investigate the potential role of B cells in the pathogenesis of Primary Sjögren's Syndrome (pSS) by analyzing cell types, differentially expressed genes, and associated signaling pathways using single-cell RNA sequencing. Methods:Peripheral blood mononuclear cells (PBMCs) from 3 pSS patients and 3 healthy controls (HCs) were collected. Single-cell transcriptomic analysis was performed, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, transcription factor analysis, pseudotime analysis, cell communication analysis, and B cell receptor (BCR) repertoire analysis. Genes and pathways potentially involved in the pathogenesis of pSS were identified, and key genes were validated by qRT-PCR. Statistical significance was assessed using T-tests and the Wilcoxon rank-sum test, with a p-value < 0.05 considered statistically significant. Results:Single-cell RNA sequencing of peripheral blood B cells from three patients with primary Sjögren's syndrome (pSS) and three healthy controls (HCs) identified three subpopulations: memory B (Bmem), naïve B (NaiveB), and plasma cells (PlasmaCells). In pSS, differentially expressed genes were enriched in Type I interferon signaling, antigen processing/presentation, and MHC class II binding. Transcription factors related to interferon responses, including NR2F6, IRF5, STAT2, and IRF9, were upregulated. Cell-cell communication analysis highlighted frequent interactions via TNFSF10-TNFRSF10C and TGFB1-TGFBR3. Pseudotime analysis indicated accelerated NaiveB differentiation along the effector branch. B cell receptor repertoire analysis revealed increased IGHV4-34 usage and higher IGHJ4/IGHJ6 usage in PlasmaCells, with reduced IGHV1-3, IGHV1-69D, and IGHV2-7D usage. qRT-PCR validation in 22 pSS patients and 22 HCs confirmed significant ISG15 upregulation (p < 0.0001). Conclusion:B cells contribute to the pathogenesis of pSS through the Type I IFN signaling pathway mediated by genes such as ISG15, alterations in BCR clonality, IGHV-J gene rearrangements, and abnormal gene usage.

Non-obstructive azoospermia (NOA) is a severe form of male infertility. Proteins from the Tre2-Bub2-Cdc16 (TBC) family emerge as key contributors to spermatogenesis, including TBC1D20, TBC1D21, and TBC1D25. Nonetheless, the specific role of TBC1D8 in male male fertility remains unclear. Our study aims to elucidate the relationship between TBC1D8 and male infertility in humans and mice. Male Tbc1d8 -/- mice were completely infertile, producing no offspring. They exhibited spermiogenesis defects from steps 9 to 16, accompanied by pronounced acrosomal abnormalities during sperm maturation, ultimately preventing the formation of functional spermatozoa. Mechanistically, TBC1D8 deficiency impaired autophagic flux and enhanced apoptosis in the seminiferous epithelium through disrupted coupling with RAB8A, culminating in azoospermia and infertility. Consistent with the murine phenotype, whole-exome sequencing (WES) identified compound heterozygous missense variants in TBC1D8 (NM_001102426.3) among three patients from unrelated Chinese Han families diagnosed with NOA or cryptozoospermia: Patient 1: c.3322A>G and c.1747C>T; Patient 2: c.3322A>G and c.2566A>G; Patient 3: c.845C>T and c.2525C>T. Histological examination of patient testicular biopsies revealed severely disrupted spermatogenic architecture and markedly reduced TBC1D8 expression, suggesting a loss-of- function effect. Together, our findings establish TBC1D8 as a previously unrecognized regulator of spermatogenesis, where its deficiency leads to NOA through impaired autophagy and increased apoptosis..

Diabetes and its complications cause serious global health and economic burdens. Various medicine-food plant polysaccharides (MFPPs) have garnered increasing attention due to their low toxicity, minimal side effects, and efficacy in suppressing hyperglycemia and reversing insulin resistance, positioning them as potential antidiabetic agents. These polysaccharides enhance gut barrier integrity, improve gut microbiota diversity, and ameliorate metabolic disorders linked to intestinal flora dysregulation in Type 2 diabetes mellitus, thereby achieving glycemic control. This review outlines the sources, antidiabetic mechanisms, and gut-modulatory effects of polysaccharides from medicinal plants. Specific polysaccharides, including Astragalus polysaccharides, Ginseng polysaccharides, Pueraria lobata polysaccharides, and Lycium barbarum polysaccharides, demonstrate the ability to repair intestinal barrier damage, prevent gut microbiota dysbiosis, and promote short-chain fatty acid (SCFA) accumulation. Additionally, the advantages of MFPP nanoparticles and their role in diabetes regulation via gut modulation are summarized. This review provides novel insights for designing dietary formulations for diabetic patients and serves as a reference for clinical applications of these polysaccharides as therapeutic or adjunctive interventions.

Artemisinin is the key component of Artemisinin-based combination therapy (ACT) for malaria. Combinations of artemisinin with partner drugs demonstrate significant therapeutic potential in various diseases, including cancer. However, the precise mechanisms by which artemisinin, in combination with partner drugs, induces cell death are still not fully understood. Ferroptosis, a distinct form of cell death characterized by its dependence on iron, oxygen, and phospholipids (PLs), represents one potential pathway. In this study, we discovered that dihydroartemisinin (DHA), the active metabolite of artemisinin and its derivatives, sensitizes cells to ferroptosis induced by GPX4 inhibition. Through integrated data analysis and experimental validation, we found that DHA enhances ferroptosis sensitivity by promoting heme oxygenase 1 (HMOX1, HO-1)-mediated mitochondrial oxidative stress, thereby triggering a feedback loop that promotes mitochondrial fusion. These results broaden our understanding of the mechanisms of DHA in combination with partner drugs, and provide insights for clinical translation of ferroptosis.

In differential MEMS resonant sensors, a pair of resonators are interconnected with other structural components while sharing a common substrate. This leads to mutual coupling of vibration energy between resonators, interfering with their frequency outputs and affecting the sensor's static performance. This paper aims to model and analyze the vibration coupling phenomena in differential common-based MEMS resonators (DCMR). A mechanical model of the DCMR structure was established and refined through finite element simulation analysis. Theoretical calculations yielded vibration coupling curves for two typical silicon resonant accelerometer (SRA) structures containing DCMR: SRA-V1 and SRA-V2, with coupling stiffness values of 2.361 × 10-4 N/m and 1.370 × 10-2 N/m, respectively. An experimental test system was constructed to characterize the vibration coupling behavior. The results provided coupling amplitude-frequency characteristic curves and coupling stiffness values (7.073 × 10-4 N/m and 1.068 × 10-2 N/m for SRA-V1 and SRA-V2, respectively) that validated the theoretical analysis and computational model. This novel approach enables effective evaluation of coupling intensity between 5resonators and provides a theoretical foundation for optimizing device structural designs.

INTRODUCTION:Allergic rhinitis (AR) is a chronic inflammatory and reactive disease of the nasal mucosa mediated by immunoglobulin E following exposure to allergens in atopic patients. The primary mediator involved is histamine release, and various immune-active cells and cytokines contribute to the inflammatory response. The condition is characterized by nasal itching, sneezing, hypersensitivity, and swelling of the nasal mucosa. Dust mites are prevalent allergens in China, and both genetic and environmental factors contribute to the development of AR. Discovering sensitizing allergens is crucial for prevention and treatment. Recent research has focused on the role of noncoding RNAs like miRNA and lncRNA in AR. These noncoding RNAs can interact within a competing endogenous RNA (ceRNA) network, influencing gene expression. METHODS:In this study, clinical samples were collected from patients with dust mite-sensitized AR and from healthy controls. Full transcriptome sequencing and PCR verification were conducted, and the verified lncRNAs were assessed for their potential as predictors of AR risk. RESULTS:ROC curve analysis demonstrated that combining two highly expressed lncRNAs (NONHSAT159281.1 and NONHSAT123298.2) provided high diagnostic accuracy. Correlation analyses revealed a positive association between NONHSAT159281.1 expression and the severity of AR symptoms, particularly nasal congestion and runny nose. Furthermore, associations between lncRNA and miRNA, as well as between miRNA and mRNA, were investigated. A ceRNA network was developed, highlighting the involvement of hsa-miR-205-5p. CONCLUSION:Overall, this research discovers potential diagnostic and therapeutic targets for AR and provides directions for future studies.

BACKGROUND:As a unique cell death modality mediated by multifaceted PANoptosome complexes, PANoptosis plays a crucial role in the development, invasion, and drug resistance of cancers. However, there is a lack of mechanisms for the PANoptosis in lung adenocarcinoma (LUAD). METHODS:More than 1500 biopsy samples of LUAD and other cancers were collected from diversified cohorts in various databases. Ten machine-learning methodologies were combined into 101 algorithm combinations to establish the prognostic model. The landscape of tumor immune microenvironment (TIME) and response to immunotherapy were assessed across the bulk-transcriptome profile utilizing different algorithms. Single-cell RNA sequencing unveiled one crucial gene as the risk factor of LUAD, which was verified and explored the potential biological mechanisms in vitro and in vivo . RESULTS:In our research, the PANoptosis Score (PAN Score) can be regarded as an independent prognostic factor for LUAD, which outperformed other clinical features and previously published literatures. Integrating PAN Score with other clinical features into a nomogram enhanced the predictive accuracy. Meanwhile, patients with high PAN Score exhibited a suppressed TIME, less tumor-infiltrated lymphocytes, and resistance to immunotherapy and chemotherapy. As the crucial contributor of PAN Score, deficiency of 14-3-3γ (YWHAG) impaired LUAD progression significantly in vitro and in vivo , enhanced the sensitivity to chemotherapy, as well as activated the PANoptosis via decreasing the concentration of vasopressin. CONCLUSIONS:Briefly, PAN Score is a robust biomarker for the prediction of prognosis and therapy response in LUAD patients. The YWHAG-vasopressin-PANoptosis axis may become the potential therapeutic target for LUAD.