ObjectivesEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are established first-line treatments for advanced non-small cell lung cancer (NSCLC) harboring common sensitizing EGFR mutations, such as exon 19 deletions (19del) and the exon 21 p.L858R point mutation. However, evidence regarding the efficacy of first-, second-, and third-generation EGFR-TKIs against uncommon EGFR exon 19 mutations, specifically p.L747P and p.L747S, remains limited, and the underlying mechanisms are not fully elucidated. This study aimed to evaluate the clinical efficacy of different-generation EGFR-TKIs in NSCLC patients harboring EGFR p.L747P or p.L747S mutations by integrating our institutional cases with published evidence.Materials and methodsWe identified patients with NSCLC harboring EGFR p.L747P or p.L747S mutations detected by next-generation sequencing (NGS) between 2020 and 2025 and retrospectively collected their clinical data. A literature review was conducted to identify and integrate relevant published case data.ResultsAmong seven treated stage IV NSCLC patients with the p.L747P mutation, two who received second-generation EGFR-TKIs as first-line therapy had an objective response rate (ORR) of 0% and experienced rapid disease progression. In contrast, six patients received third-generation EGFR-TKIs as first- or second-line therapy, with two achieving stable disease (SD) and one achieving partial response (PR), with a substantially longer progression-free survival (PFS) of 12 to 40 months. Separately, six patients were found to harbor the p.L747S mutation concomitantly with a common TKI-sensitive mutation, none of whom had received prior EGFR-TKI therapy. Of these, two patients were treated with a third-generation TKI: 1 achieved SD and the other achieved partial response (PR).ConclusionsThis integrated retrospective analysis suggests that third-generation EGFR-TKIs may provide disease control (PR/SD) and prolonged PFS in a subset of NSCLC patients harboring uncommon EGFR p.L747P or p.L747S mutations, particularly those with co-existing sensitizing mutations or central nervous system metastases (CNS).

Tumour immune regulation has traditionally been interpreted through immune cell states, metabolic reprogramming, and genomic alterations. Although this framework has advanced cancer immunology, it does not fully explain the marked heterogeneity of the tumour immune microenvironment or the poor response of many immunologically “cold” tumours to immune checkpoint blockade. Emerging evidence identifies the nervous system as an important but underappreciated regulator of tumour immunity. Many solid tumours are densely innervated by sympathetic, parasympathetic, and sensory nerves, and increased neural fiber density is frequently associated with immunosuppression, tumour progression, and metastasis. Through predominantly non-synaptic signalling, neurotransmitters and neuropeptides modulate immune cell recruitment, T cell activity, myeloid polarization, and immune tolerance within the tumour microenvironment. Neural signals also reshape tumour metabolism, establishing a neuro–immune–metabolic axis that converts transient neural inputs into sustained immunosuppressive states and self-reinforcing feedback loops linked to therapeutic resistance. At the systemic level, the central nervous system further influences tumour immunity through stress-related neuroendocrine pathways and behavioral states. In this Review, we summarize current knowledge on tumour innervation, neuro–immune crosstalk, and their metabolic basis, and discuss how neural regulation may shape immunotherapy responses and offer new opportunities for precision immunomodulation in cancer.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder primarily characterized by persistent airflow obstruction. This study investigates the prevalence and risk factors of pre-bronchodilator airflow obstruction among general population aged 40 years or older in Southwest China. This is a cross-sectional baseline analysis of an ongoing multi-center population-based cohort study in Southwest China. A total of 22,575 participants aged 40 years or older, recruited from four centers between April 2020 and June 2022, were included in the analysis. All participants had valid pre-bronchodilator spirometry results. Airflow obstruction was defined primarily as an FEV₁/FVC ratio below the Global Lung Function Initiative lower limit of normal. The prevalence of airflow obstruction was assessed and compared across subgroups. Risk factors were identified using univariate and multivariable logistic regression analyses. The overall prevalence of airflow obstruction was 14.9

The molecular basis of neutrophil-driven immunopathology in severe coronavirus disease 2019 (COVID-19) remains poorly defined. Here, we identify the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) SARS-unique domain (SUD)2core domain as a direct binding partner of the neutrophil-associated protein heme binding protein 2 (HEBP2). We show that HEBP2 normally suppresses azurophilic granule exocytosis, whereas SUD2core recruits the E3 ligase LTN1 to ubiquitinate and degrade HEBP2, thereby activating the Rab27a-Synaptotagmin Like 1 (SYTL1) axis to promote granule release, NETosis, and pro-inflammatory cytokine secretion. In a human immuno-epithelial organoid co-culture model, SUD2core amplifies epithelial damage in an HEBP2-dependent manner. Importantly, two small-molecule compounds that disrupt the SUD2core-HEBP2 interaction effectively attenuate neutrophil-mediated inflammation. These findings reveal a viral strategy that dismantles host restraint on neutrophil effector functions and highlight the SUD2core-HEBP2 interface as a promising therapeutic target for COVID-19.

The dynamic immune landscape within the tuberculous (TB) granuloma microenvironment critically governs antibiotic penetration efficiency, bacterial persistence, and long-term therapeutic outcomes. Herein, we present a macrophage-targeted inhalable nanoemulsion for co-delivering rifampicin and LCL161, an inhibitor of apoptosis protein antagonist. Inhaled mannose-nanoemulsions (named RL-NE@Man) enable granuloma-targeted delivery in TB mice model, increasing infected macrophage apoptosis, remodeling the tuberculosis microenvironment, and promoting T-cell immunity to synergize with antibiotics for the eradication of granulomas and persistent Mycobacterium tuberculosis infection. Following two-dose inhalational administration, RL-NE@Man displayed potent bactericidal activity against M. tuberculosis while concurrently alleviating pulmonary pathological lesions and hyperinflammatory responses, demonstrating superior bacterial suppression efficacy compared with that of the first-line rifampicin monotherapy. This inhaled combination therapy, which integrates immunomodulators with antibiotics to modulate the local immune landscape and synergistically enhance bactericidal efficacy, represents a novel therapeutic strategy for precision tuberculosis management.

Background and Objective:Lung cancer remains the leading cause of cancer-related death worldwide. Many patients are still facing limited treatment benefit or therapeutic resistance. Single-cell RNA sequencing (scRNA-seq) enables high-resolution characterization of cellular states, whereas spatial transcriptomics (ST) preserves tissue architecture and maps gene expression within the tumor microenvironment (TME). This review summarizes recent advances in scRNA-seq and ST in lung cancer and discusses how these technologies have improved our understanding of tumor biology and therapeutic response. Methods:A literature search was conducted in PubMed/MEDLINE for English-language studies published between January 2020 and 2025 using terms related to lung cancer, single-cell sequencing, single-nucleus sequencing, and spatial transcriptomics. Key Content and Findings:Recent studies have used scRNA-seq and ST to characterize immune and stromal compartments, tumor cell heterogeneity, early cancer evolution, metastasis, and treatment-associated remodeling. These findings suggest that lung cancer progression is shaped not only by genetic alterations but also by transcriptional plasticity, spatially organized TME niches, and dynamic interactions between tumor, immune, and stromal cells. Conclusions:scRNA-seq and ST have shifted lung cancer research from bulk tumor profiling toward cellular and spatial ecosystem analysis. However, many proposed biomarkers and therapeutic targets remain exploratory. Further spatial validation, functional experiments, and clinically annotated cohorts are needed before these findings can be translated into routine precision medicine.

Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has demonstrated efficacy across multiple treatment lines for patients with EGFR-mutated non-small cell lung cancer (NSCLC). However, the optimal treatment sequence and comparative effectiveness vs alternative therapies remain unclear. Methods: A systematic review and meta-analysis was conducted following the PRISMA 2020 guidelines. Embase, Medline (via Ovid), PubMed, Cochrane Central Register of Controlled Trials, Web of Science, and Google Scholar were searched from inception to May 31, 2025. Clinical trials comparing osimertinib with other treatments (placebo, EGFR-tyrosine kinase inhibitors [TKIs], chemotherapy, targeted therapy) in patients with EGFR-mutated NSCLC were included. Primary outcomes included objective response rate (ORR), median progression-free survival (mPFS), disease control rate (DCR), overall survival (OS), and adverse events. Subgroup analyses were performed by treatment line and comparator type. Risk of bias was assessed using the Cochrane RoB 2 tool. Statistical analysis was performed using R version 4.5.0 with random-effects models for high heterogeneity (I 2 > 50%). Results: Sixteen studies encompassing 4931 patients were included. Osimertinib demonstrated significantly superior ORR compared to control treatments (relative risk [RR] = 1.59, 95% confidence interval [CI] = 1.16 to 2.17, P < .001), exceeding the minimal clinically important difference threshold. The mPFS benefit was substantial (standardized mean difference [SMD] = 4.53 months, 95% CI = 1.23 to 7.82, P < .0001), with greater improvements observed in first-line therapy (SMD = 3.25, 95% CI = 0.52 to 5.97) vs second-line treatment (SMD = 7.61, 95% CI = −10.08 to 25.30). The DCR was significantly improved (RR = 1.26, 95% CI = 1.05 to 1.52, P < .0001). The OS showed modest but consistent improvement (SMD = 0.18, 95% CI = 0.11 to 0.26, P < .0001) with no heterogeneity (I 2 = 0%). Osimertinib was most effective vs chemotherapy and showed consistent benefits vs first-generation TKIs. Adverse events included increased upper respiratory tract infections, skin toxicities, and QT prolongation, while nausea and alopecia were reduced. Conclusions: Osimertinib demonstrates superior efficacy across multiple endpoints in patients with EGFR-mutated NSCLC, with benefits observed in both first-line and second-line settings. The treatment provides clinically meaningful benefits with a manageable safety profile, supporting its use as a preferred therapeutic option across different treatment sequences.

Respiratory diseases cause significant morbidity, yet diagnosis remains labor intensive and dependent on physician expertise. Here, we present LungGPT, a unified multimodal system trained on 147 million tokens of domain-specific electronic health records from 125,917 participants. LungGPT comprises two modules: LungGPT-Dx for respiratory disease diagnosis and early warning of critical illness, and LungGPT-Ex for interpretable diagnostic reasoning and treatment recommendations. In large-scale evaluations, LungGPT-Dx achieves a macro-average area under the curve (AUC) of 0.852 (95% confidence interval [CI]: 0.839-0.865) across 22 respiratory diseases, with disease-specific AUCs exceeding 0.900 for lung cancer and pulmonary tuberculosis. Crucially, the model further improves early warning of critical illness by incorporating chain-of-thought (CoT) reasoning into textual data and integrating computed tomography (CT) imaging features. LungGPT-Ex generates high-quality, interpretable reasoning that outperforms specialized clinical models and matches advanced general-purpose models such as GPT-4o and DeepSeek-R1 in correctness, completeness, and truthfulness. By bridging precision diagnostics and rapid decision-making, LungGPT provides a standardized framework to enhance clinical workflows and improve patient outcomes in respiratory healthcare.

INTRODUCTION:Lung cancer remains a leading cause of cancer mortality globally, emphasising the critical need for non-invasive and cost-effective early screening methods. Breath analysis, detecting disease-specific volatile organic compounds (VOCs), presents a promising diagnostic avenue. METHODS:This cross-sectional study enrolled 4515 participants, including 4099 nonmalignant controls and 416 lung cancer patients. Exhaled breath samples were analysed using proton transfer reaction time-of-flight mass spectrometry (PTR-TOF MS). Machine learning algorithms, particularly Light Gradient Boosting Machine (LGBM), were employed to construct classification models for distinguishing lung cancer from healthy controls and early-stage lung cancer from benign pulmonary nodules. Model interpretability was assessed using SHAP values. RESULTS:The LGBM model demonstrated superior performance, achieving 95% sensitivity, 98% specificity, and 98% accuracy for discriminating lung cancer from healthy controls. For the clinically challenging task of distinguishing early-stage lung cancer from benign nodules, LGBM achieved 97% sensitivity, 98% specificity, and 98% accuracy. SHAP analysis identified alpha-pinene (m/z 137) and methyl methacrylate (m/z 101) as the most significant VOCs. CONCLUSION:This large-scale study validates PTR-TOF MS based breath analysis combined with machine learning as a robust, non-invasive tool for early lung cancer detection. The LGBM model, supported by SHAP interpretability, offers high diagnostic accuracy in large cohorts. Future work will expand to diverse histological subtypes and multicenter validation. TRIAL REGISTRATION:ChiCTR2500101879.

Abstract Lung cancer, the leading cause of tumor-related mortality worldwide, poses a severe threat to public hygiene. Advances in precise personalized treatment strategies, such as targeted therapy and immunotherapy, present promising prospects for lung cancer cure. Nonetheless, owing to the undefined underlying mechanism of carcinogenesis and unpredictable treatment efficacy, the overall management of lung cancer remains a great concern. N 6-methyladenosine (m6A), identified as pervasive and conserved eukaryotic transcriptional epigenetic modification, has been revealed to exert a noneligible influence on many biological processes through regulation of ribonucleic acid (RNA) splicing, degradation, and translation. Furthermore, intensive investigations suggest that the m6A modifications and subsequent alterations to transcripts may be involved in the occurrence and progression of various tumors. In this review, we provide the newest insight into the role of m6A modification in lung cancer, focusing on its impact on progression, treatment regulation, and prognosis prediction, which may guide future research based on m6A to discover more novel therapeutic targets to combat this fatal disease.

Background The IASLC grading system has prognostic utility and potential therapeutic implications in invasive non-mucinous lung adenocarcinoma (LUAD), but the molecular basis underlying the grading spectrum remains unclear. Methods We performed whole-genome sequencing and transcriptomic profiling in 138 Chinese patients with invasive non-mucinous LUAD to systematically characterize the molecular features across grades, including coding driver events, mutational signatures, non-coding regulatory disruptions, and transcriptional programs. Results Compared with Grade 1–2 tumors, Grade 3 LUADs exhibited heightened invasive potential, manifested by more advanced stage, more frequent spread through air spaces, and independently worse survival. Grade 3 tumors had elevated tumor mutational burden and were enriched for alterations in genome maintenance and cell-cycle genes, including TP53, as well as genes implicated in DNA damage response, including ZFHX4. APOBEC-associated mutagenesis was selectively enriched in Grade 3 tumors independent of smoking status, consistent with an instability-associated phenotype. Recurrent non-coding regulatory disruptions affected lung lineage-defining genes, particularly surfactant-associated genes, and were correlated with reduced expression. Transcriptomic profiling revealed epithelial dedifferentiation, loss of pulmonary homeostatic programs, and activation of proliferative and stress-related pathways. Notably, MUC16 emerged as a convergent event linking genomic and transcriptional dysregulation, with missense mutations associated with higher expression and increased expression in Grade 3 tumors correlating with the proportion of high-grade histologic patterns. Conclusions These findings provide a molecular framework for the IASLC grading spectrum and identify Grade 3 LUAD as a distinct instability-associated and dedifferentiated biological state.

Utilizing CAR-T cells to eliminate circulating tumor cells (CTCs) and inhibit metastasis is a promising strategy. However, this approach is hindered by the lack of specific antigens. Membrane-bound HSP70 (mHSP70) is commonly expressed on the cell membrane of numerous tumor types, notably on CTCs, making it an ideal target for CAR-T therapy to treat these malignancies and prevent metastasis. Here, we generated CAR T cells based on natural ligand granzyme B (GrB-CAR T) targeting mHSP70. GrB-CAR T cells exhibited potent cytotoxicity against a broad spectrum of cancer cell lines and stem-like cancer cells in vitro and effectively inhibited xenograft tumor growth in vivo. Importantly, CTCs maintain mHSP70 expression in xenograft models, and GrB-CAR T cells markedly decreased the number of CTCs, thereby preventing cancer metastasis. Moreover, despite human granzyme B exhibits cross-reactivity with mouse and macaque mHSP70—particularly given the complete homology between macaque and human mHSP70—no obvious adverse effects were observed in the animals treated with GrB-CAR T cells. These results demonstrate GrB-CAR T cells as a safe and effective approach with broad-spectrum anticancer activity and provide compelling experimental evidence for CAR T cell-mediated metastasis inhibition through targeting CTCs.

Background: Lung adenocarcinoma (LUAD) represents a major clinical challenge due to its high recurrence and metastasis rates, with the underlying molecular mechanisms yet to be fully elucidated. Despite therapeutic advances, the prognosis of recurrent LUAD remains dismal, creating an urgent demand for novel therapeutic targets. Preferentially expressed antigen in melanoma (PRAME) holds oncogenic potential, but its role in LUAD recurrence and metastasis warrants comprehensive investigation. Therefore, this study aims to systematically investigate the function of PRAME in early-stage LUAD recurrence and metastasis, elucidate its upstream epigenetic regulation and downstream signaling pathways, and identify potential targets for precision therapy in high-risk patients. Methods: To explore the role of PRAME in LUAD, we performed integrative transcriptomic and clinical analyses to assess PRAME expression patterns and their clinical correlation in primary tumor tissues. Functional validation was conducted using female BALB/c nude mouse metastatic and subcutaneous xenograft models to clarify the effects of PRAME on tumor progression. Mechanistic investigations focused on the association between PRAME and epithelial-to-mesenchymal transition (EMT), as well as the PI3K/ AKT/mTOR signaling pathway. Chromatin immunoprecipitation (ChIP) assays were used to verify ZNF740 binding to the PRAME promoter, and CRISPRon/CRISPRoff-mediated epigenetic editing experiments were performed to interrogate the regulatory role of promoter methylation in PRAME expression. Results: Transcriptomic and clinical analyses revealed significant upregulation of PRAME in recurrent primary tumor tissues, and high PRAME expression was strongly associated with reduced recurrence-free survival (RFS). Functional experiments using xenograft models confirmed that PRAME plays an important role in LUAD progression and metastasis. Mechanistically, PRAME exerts its oncogenic effects by inducing EMT and activating the PI3K/AKT/mTOR signaling pathway. ZNF740 was identified as a direct transcriptional activator of PRAME, and ChIP assays confirmed that ZNF740 binds to the PRAME promoter in a manner dependent on DNA hypomethylation. Additionally, CRISPRon/CRISPRoff-mediated experiments demonstrated that PRAME expression is dynamically and bidirectionally regulated by promoter methylation. Conclusions: Collectively, this study establishes a comprehensive mechanistic framework: DNA hypomethylation facilitates ZNF740 binding to the PRAME promoter, driving PRAME activation, which in turn promotes early-stage LUAD metastasis through the induction of EMT and the activation of the PI3K/ AKT/mTOR signaling pathway. These findings support the notion that PRAME might serve as a candidate prognostic biomarker and therapeutic target for recurrent LUAD.

The clinical efficacy of immunotherapy in advanced esophageal squamous cell carcinoma (ESCC) remains suboptimal, as most patients eventually develop drug resistance and experience disease progression. Here, we identify Collagen Triple Helix Repeat Containing 1 (CTHRC1) as a critical mediator of immunotherapy resistance in ESCC. Elevated CTHRC1 expression was observed in tumors unresponsive to immune checkpoint blockade and was associated with enhanced platelet activity and infiltration of megakaryocytes (MKs) into the tumor microenvironment. Mechanistically, CTHRC1 facilitated MK activation and recruitment, fostering an immunosuppressive niche that impaired cytotoxic T-cell activity and promoted cell exhaustion. To therapeutically target this axis, we developed a lipid nanoparticle (LNP)-encapsulated mRNA vaccine encoding CTHRC1. In preclinical ESCC models, the CTHRC1-mRNA-LNP vaccine elicited robust antitumor immunity. Notably, the combination of CTHRC1-mRNA vaccination with anti–PD-1 therapy induced synergistic intratumoral T-cell infiltration, depletion of MKs, reversal of immunosuppression, and durable tumor regression. Collectively, these findings uncover an unrecognized immunoregulatory function of CTHRC1 in ESCC and highlight its therapeutic targeting as a promising strategy to enhance the efficacy of immune checkpoint blockade. CTHRC1 directly engages integrin αIIbβ3 and to drive megakaryocyte and activates the TLR4–NF-κB-IL-8 axis to promote megakaryocyte/platelet infiltration, promoting an immunosuppressive ESCC TME and T-cell dysfunction. Administration of a CTHRC1 mRNA–LNP vaccine elicits potent antigen-specific humoral and cellular immunity, dismantles megakaryocyte-mediated immune exclusion, converts a cold TME into an inflamed state, and restores sensitivity to PD-1 blockade.

OBJECTIVES:To evaluate the effects of nurse-led shared decision-making (SDM) on lung cancer screening outcomes, including low-dose CT (LDCT) uptake, benign findings, early cancer detection and willingness to participate among high-risk populations. DESIGN:Systematic review and meta-analysis. DATA SOURCES:PubMed, Medline via OvidSP, Cochrane Central Register of Controlled Trials, EMBASE via OvidSP, Web of Science, Scopus, grey literature databases and clinical trial registries were searched from inception to March 2025. ELIGIBILITY CRITERIA:Studies evaluating nurse-led SDM interventions in high-risk lung cancer populations, reporting outcomes including LDCT uptake rates, screening results (Lung-RADS (Lung Imaging Reporting and Data System) classifications), early-stage cancer detection or willingness to participate. Randomised controlled trials, quasi-experimental studies and observational studies were included. DATA EXTRACTION AND SYNTHESIS:Two reviewers independently extracted data and assessed risk of bias using the Risk of Bias in Non-randomised Studies of Interventions (for non-randomised studies) and Cochrane Risk of Bias 2.0 (for randomised controlled trials). Meta-analyses were conducted using random-effects models. Meta-regression explored sources of heterogeneity. RESULTS:13 studies (n=13 608 participants) were included, comprising 10 single-arm studies and three comparative studies. In single-arm studies without control groups, nurse-led SDM programmes achieved a pooled LDCT uptake rate of 98% (95% CI 28% to 100%; I²=99%), and willingness to participate was 68% (95% CI 24% to 93%; I²=98%). In comparative studies, nurse-led SDM showed no significant difference in LDCT uptake compared with usual care (RR 1.00, 95% CI 0.99 to 1.02; I²=0%), suggesting non-inferiority rather than superiority. Among individuals who completed screening, 81% (95% CI 77% to 85%) had benign or low-risk findings (Lung-RADS [Lung Imaging Reporting and Data System] I/II), and 2% (95% CI 1% to 3%) were diagnosed with early-stage lung cancer, rates consistent with benchmark screening trials. Meta-regression identified female sex as positively associated with uptake (β=0.54, p<0.001), while current tobacco use was negatively associated (β=-0.37, p=0.033). The risk of bias was moderate to serious across studies. CONCLUSIONS:Comparative evidence suggests that nurse-led SDM achieves equivalent LDCT uptake to standard care approaches, indicating feasibility as an alternative service delivery model. However, the predominance of single-arm studies, high heterogeneity and moderate-to-serious risk of bias limit causal inference. High uptake rates in single-arm studies likely reflect selection bias rather than intervention effectiveness. Current evidence supports the feasibility but not the superiority of nurse-led SDM. Well-designed randomised controlled trials are needed to establish comparative effectiveness and cost-effectiveness before recommending widespread integration of nurse-led SDM into lung cancer screening programmes. TRIAL REGISTRATION NUMBER:PROSPERO CRD420251033595. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=1033595.

Summary Lower levels of sitting time were associated with a lower risk of severe asthma exacerbations in adults. High levels of physical activity eliminated the detrimental association of sitting time with severe asthma exacerbations in adults.

Background:Early identification of Pre-chronic obstructive pulmonary disease (pre-COPD) is vital for preventing irreversible lung damage. However, despite its high prevalence, there is a lack of practical tools to predict which individuals will progress to spirometry-defined COPD. This study aimed to identify independent risk factors and develop a clinical nomogram to quantify the risk of disease progression in a pre-COPD population. Methods:We conducted a multicenter, retrospective cohort study in Southwest China (2019-2023), enrolling 1088 participants with pre-COPD. Baseline data, including demographic information, smoking status, comorbidities, lung function, and hematological and biochemical indicators, were analyzed. Independent predictors were identified via multivariate logistic regression, and a risk-prediction nomogram was constructed and validated. Results:During follow-up, 54.6% of participants progressed to COPD. The final prediction model identified six independent risk factors: age (OR=1.043), hypertension (OR=2.331), diabetes (OR=2.412), hemoglobin level (OR=1.016), lymphocyte count (OR=0.639), and basophil count (OR=1.411). The nomogram demonstrated robust discriminative ability, with an AUC of 0.758 in the training set and 0.718 in the validation set. Calibration curves showed high consistency, and Decision Curve Analysis (DCA) confirmed significant clinical net benefit. Conclusion:Progression from pre-COPD to spirometry-defined COPD is highly prevalent and driven by age, comorbidities, and systemic inflammatory markers. Our validated nomogram provides a precise, non-invasive tool for clinicians to identify high-risk individuals, enabling targeted early intervention and optimized resource allocation in COPD prevention.

Background The pathogenic mechanisms underlying metabolic dysfunction-associated steatohepatitis (MASH) are highly complex and multifactorial, and there are limited pharmacological therapies proven effective for clinical use. Although the natural product wedelolactone (WED) demonstrates potential hepatoprotective effects, its therapeutic efficacy in MASH and the underlying mechanisms remain poorly understood. Purpose This study investigates the therapeutic efficacy of WED in ameliorating diet-induced MASH and aims to elucidate its direct molecular targets and underlying mechanisms. Methods To investigate the therapeutic potential of WED in MASH, this study established an in vitro model of lipid accumulation and inflammatory response by treating HepG2 cells and primary mouse hepatocytes with palmitic acid (PA) and oleic acid (OA), thereby assessing the in vitro effectiveness of WED. Additionally, we employed the MCD diet- and HFHC diet-induced mouse MASH models to evaluate the therapeutic effects of WED. To identify its molecular targets, we synthesized biotin-labeled WED probes and screened potential direct binding proteins using a human proteome microarray. The binding affinity was validated by surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA). Molecular dynamics simulation and molecular docking were performed to determine the key interaction sites between WED and its targets. Transcriptomic and bioinformatics analyses were integrated to elucidate the downstream signaling pathways regulated by WED through these targets. Finally, biological functional assays were performed to validate the underlying mechanism of WED. Results This study has demonstrated that WED exerts a significant anti-MASH effect by directly targeting SORBS1, with binding occurring at VAL32 and HIS47. The underlying mechanism involves the direct binding and activation of SORBS1 by WED, leading to multiple regulation of downstream signaling pathways. Specifically, WED regulates the expression of SORBS1 in liver tissue, improves glycolipid metabolism through the CBL/TC10/GLUT4 axis, and suppresses proinflammatory cytokines such as TNF-α and IL-6. This coordinated action results in effective alleviation of hepatic lipid accumulation, inflammation, and fibrosis. Furthermore, inhibiting SORBS1 exacerbates the MASH process and completely abolishes the efficacy of WED, thereby confirming that SORBS1 is the key target for its therapeutic effect. Conclusion Here, this study reveals that WED ameliorates insulin resistance and suppresses hepatic inflammation and fibrosis by directly binding to SORBS1, thereby significantly attenuating the progression of MASH. These findings establish SORBS1 as a potential novel therapeutic target for MASH and provide a potential candidate compound for the advancement of therapies targeting MASH.

BACKGROUND:The triglyceride-glucose (TyG) index is a new alternative marker for insulin resistance and metabolic dysfunction, which has recently been linked to lung health. However, the link among the TyG index, type 2 (T2) inflammation, and asthma is largely unexplored. OBJECTIVES:To explore clinical, inflammatory characteristics and exacerbations in patients with asthma grouped by the TyG index with or without T2 inflammation. METHODS:This was a prospective cohort study with 12-month follow-up based on the Australasian Severe Asthma Network. Patients with stable asthma were divided into the TyGlow and TyGhigh groups by the 75th percentile values of the TyG index. Subgroups were analyzed based on T2 status. All participants with stable asthma (n = 626) underwent multidimensional assessment and sputum induction. Univariate and multivariable negative binomial regression analyses were used to examine the relationship between asthma exacerbations and TyG index with or without T2 inflammation. RESULTS:Patients with asthma in the TyGhigh group (n = 156) had higher body mass index, worse metabolic function and airway obstruction, more comorbidities including diabetes and metabolic syndrome, and increased risk of exacerbations independent of T2 inflammation, compared with the TyGlow group (n = 470). Furthermore, the TyGhigh T2low group was at significantly increased risk of moderate-to-severe exacerbations (adjusted incidence rate ratio [IRR] = 2.54, 95% confidence interval [CI] = [1.56, 4.15], P < .001), emergency visits (adjusted IRR = 7.88, 95% CI = [2.71, 22.92], P < .001), and unscheduled visits (adjusted IRR = 2.87, 95% CI = [1.65, 4.98], P < .001). CONCLUSIONS:The TyG index is a promising biomarker of asthma exacerbations, highlighting the clinical relevance of assessing the TyG index in asthma management.