BackgroundPulmonary fibrosis (PF) is an irreversible and lethal lung disease characterized by progressive scarring lacking safe and effective treatment options. Recent studies have underscored the role of macrophage polarization in fibrotic progression, yet the role of kynurenine (Kyn), a metabolite of tryptophan (Trp), in macrophages during PF progression remains elusive.MethodsLiquid Chromatography-tandem Mass Spectrometry (LC-MS) analysis was used to detect tryptophan metabolism changes in the serum of PF patients and control subjects. Macrophage-specific Ido1 or Ahr deletion mice was utilized to explored the role of Kyn in the bleomycin-induced fibrotic mouse model and ChIP sequence was employed to elucidate the mechanism by which Kyn inhibits pro-fibrotic macrophage activation.ResultsWe identified Kyn, Trp levels and Kyn/Trp ratio (KTR) were notably elevated in the serum of patients with different types of PF and these alterations were inversely correlated with lung function. Although such elevation might appear pathogenic, our functional studies demonstrate that Kyn exerts protective effects in PF, akin to brain natriuretic peptide in heart failure. Macrophage-specific deletion of Ido1 or aryl hydrocarbon receptor (AhR, the receptor of Kyn) exacerbated bleomycin-induced PF, while exogenous Kyn supplementation mitigated disease severity. Mechanistically, Kyn bound to the AhR, facilitating its nuclear translocation, where it promoted Slc39a10 transcription to increase the intracellular levels of zinc ion, thereby inhibiting profibrotic macrophage differentiation. Intriguingly, pirfenidone was noted with high potency to suppress Kyn production and our studies demonstrated that administration of Kyn along with pirfenidone effectively enhanced the therapeutic efficacy against PF.ConclusionsIn summary, these findings reveal a previously unrecognized Kyn-AhR-SLC39A10-Zn2+ signaling axis that governs macrophage polarization in PF, and unveiled the importance of Trp metabolism in PF pathogenesis, which could be novel therapeutic strategies against PF.

BACKGROUND:Hypoxic pulmonary hypertension (HPH) is a representative vascular remodeling disease with a poor prognosis. Previous findings from our study have implicated the NICD4 (Notch4 intracellular domain) in pulmonary artery smooth muscle cells (PASMCs) in the pathogenesis of HPH. However, the underlying regulatory mechanisms remain unclear. In this study, we aimed to elucidate the potential regulatory mechanism of NICD4 in HPH. METHODS:Using coimmunoprecipitation combined with mass spectrometry, we identified USP8 (ubiquitin-specific peptidase 8) as a novel binding protein of NICD4 in PASMCs. The functional role of USP8 was investigated in vivo using smooth muscle cell-specific Usp8 knockout (Usp8Acta2-/-) mice and in vitro using primarily cultured PASMCs, alongside pharmacological inhibition with DUB-IN-2 (deubiquitinase-inhibitor-2). RESULTS:USP8 was significantly upregulated in lung tissues from patients with HPH due to interstitial lung disease or chronic obstructive pulmonary disease, HPH rodent models, as well as in hypoxic PASMCs. Usp8 deficiency in Acta2-positive mice (Usp8Acta2-/-) or pharmacological inhibition of USP8 by DUB-IN-2 markedly attenuated HPH development. In vitro, USP8 knockdown suppressed hypoxia-induced PASMC proliferation, migration, and apoptosis resistance by modulating the NICD4-MAPK pathway. Mechanistically, USP8 was bound directly to NICD4 to maintain its stability by removing the K48-linked ubiquitin chain on NICD4 at lysine 1760, thus preventing proteasomal degradation. Furthermore, USP8 can be transcriptionally upregulated by CSL/NICD4 under hypoxia, forming a NICD4/USP8-positive feedback loop. CONCLUSIONS:Our study unveils a critical NICD4/USP8-positive feedback loop that drives HPH pathogenesis, highlighting the importance of ubiquitination in pulmonary vascular remodeling. Targeted disruption of this loop represents a promising therapeutic strategy for HPH.

Background Lung cancer incidence and mortality continue to rise in China, highlighting the need for a deeper understanding of its epidemiology and optimal screening targets. Methods A total of 10,560 participants with 5–30 mm pulmonary nodules incidentally detected via low-dose computed tomography (LDCT)/CT were enrolled from 23 hospitals (October 2018–May 2021) and followed for 2–3 years for evaluation of circulating tumor DNA (ctDNA) biomarkers to distinguish malignant and benign nodules. Demographic, clinical, and imaging data were collected and analyzed. Lung cancer risk factors were assessed using stepwise single and multiple-factor binary logistic regression. This study reports only the baseline epidemiological characteristics of the population and the associated risk factors of lung cancer. Results A higher proportion of females (56.56%) were present across all age groups, with a median age of 53 years (45–62), younger than males (55 years [46–63], P < 0.001). While 97.1% of females and 37.8% of males were non-smokers, and 68.65% of participants had no occupational exposure, 71.10% had a history of second-hand smoke exposure. Most nodules were solitary (81.24%), sub-centimeter (78.22%), and non-solid (62.49%). Malignancy was identified in 17.33% of nodules, with 97.32% classified as early-stage lung adenocarcinoma (AJCC stage 0–I: 90.35%). The malignant rate increased with age and nodule size and was also associated with multiple nodules, ground-glass nodules (GGNs), upper lobe location, and female sex. Proportion of patients with malignant nodules was similar between non-high-risk (21.04%) and high-risk (17.92%) groups based on current Chinese screening guidelines, while proportions of benign nodules were notably high for solid nodules (37.21%) and small nodules (20.15%). Conclusion Our large-scale investigation provides updated data to guide future precise clinical management of pulmonary nodules, with a particular focus on younger females and reducing overtreatment.

Background Patients with chronic obstructive pulmonary disease (COPD) frequently present with psychological comorbidities, including anxiety and depression, which may contribute to poorer clinical outcomes. However, the prevalence and impact of these mental health conditions in COPD patients have long been underrecognized. Leveraging data from the Chinese Population Health and Multimorbidities Study (CPHMS), a large epidemiological survey on chronic respiratory diseases in China, this study aimed to estimate the prevalence of anxiety and depression comorbidities among community-dwelling COPD patients and to evaluate the diagnostic utility of the COPD Assessment Test (CAT) scale for detecting these conditions in spirometry-confirmed COPD patients. Methods Analytical data were derived from the CPHMS. Comprehensive information on sociodemographic characteristics, lifestyle factors, and health status was collected. COPD-related pulmonary and extra-pulmonary symptoms were assessed using the CAT scale, and anxiety and depression were evaluated via the Hospital Anxiety and Depression Scale. Multivariable logistic regression was employed to identify factors associated with anxiety or depression comorbidities, and receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of the CAT scale. Results Among 3641 spirometry-confirmed community COPD patients, the prevalence of anxiety and depression was 11.07% (95% confidence interval [CI]: 10.05–12.09%) and 14.23% (95% CI: 13.09–15.36%), respectively. Female gender, rural residence, unemployment, lower annual family income, and higher total CAT score, as well as higher scores on both pulmonary and extra-pulmonary symptom subscales of the CAT, were independently associated with an increased likelihood of anxiety and/or depression in COPD patients. The diagnostic yield of the CAT scale for identifying anxiety and depression in COPD patients was evaluated. In the overall COPD patients, the optimal total CAT cut-off value for detecting anxiety was 9 (area under the ROC curve [AUC]: 0.637; 95% CI: 0.607–0.666), and for depression was 7 (AUC: 0.633; 95% CI: 0.607–0.659). Notably, among rural-dwelling COPD patients, the optimal cut-off was 7 for both anxiety (AUC: 0.624; 95% CI: 0.582–0.665) and depression (AUC: 0.616; 95% CI: 0.579–0.653), whereas in urban patients, the corresponding cut-offs were 11 for anxiety (AUC: 0.652; 95% CI: 0.610–0.694) and 10 for depression (AUC: 0.654; 95% CI: 0.618–0.691). Conclusions This study delineated the prevalence of anxiety and depression among community COPD patients and validated the clinical utility of the CAT scale in detecting these psychological comorbidities. Our findings underscore the pressing need for tailored psychological support, particularly for COPD patients residing in rural area of China.

BACKGROUND:Interferon (IFN)-stimulated gene 15 (ISG15) is a downstream molecule of the IFN pathways central to many cellular processes. ISG15 mainly exerts its function through a post-translational modification process known as ISGylation. OBJECTIVE:In this study, the role of ISG15 in the activation of hepatic stellate cells (HSCs) and liver fibrosis was examined. DESIGN:Liver fibrosis was established by carbon tetrachloride (CCl4), bile duct ligation (BDL) surgery and metabolic dysfunction-associated steatohepatitis (MASH) diet between HSC-specific deletion of ISG15 (ISG15cKO) and wild type mice. Using genetic strategies in vitro, the role of ISG15 in HSCs was established. Immunoprecipitation, luciferase reporter assays and chromatin-immunoprecipitation assays (ChIP) in combination with proteomics sequencing in HSCs were used to study the associated downstream mechanisms. RESULTS:ISG15 was underexpressed in activated HSCs and fibrotic livers, showing an inverse correlation with α-smooth muscle actin in patients with liver fibrosis. ISG15cKO mice developed spontaneous hepatic fibrosis and showed exacerbated CCl4/BDL-induced fibrogenesis. In vitro, ISG15 modulated HSC activation, proliferation and excessive extracellular matrix production. ISG15 deficiency in HSCs promoted transforming growth factorβ2 (TGFβ2) transcription by enhancing phosphorylated cAMP responsive element binding protein 1 (CREB1) activity, thereby inducing CREB1 binding on TGFβ2 promoter regions to activate TGFβ2/SMAD2 signalling. ISGylation directly binds CREB1 on Lys-304 and Lys-305 to inhibit p-CREB1 activity. Overexpression of ISG15 in HSCs or pharmacological inhibition of CREB1 by 666-15 could abolish ISG15 deficiency-induced liver fibrosis in CCl4-treated mice. CONCLUSIONS:ISG15 regulated HSC activation and liver fibrosis in part via the CREB1/TGFβ2/SMAD2 regulatory pathway. Utilisation of ISG15-CREB1 signalling may be a potential therapeutic target for liver fibrosis.

Hundreds of millions of people worldwide endure continuous suffering and significant economic burdens due to inflammatory diseases. Various acute and chronic inflammatory diseases and the natural aging of the human body are common causes of organ damage. Therefore, how to reasonably regulate inflammation, tissue repair and regeneration after organ damage has been of great concern, especially the pathological repair caused by inflammation will lead to the destruction of the original structure and function of tissues and organs. Low-intensity pulsed ultrasound (LIPUS) is a promising non-invasive physical therapy that can produce different biological effects on organs, tissues and cells. Certain clinical trials have demonstrated the outstanding capacity of LIPUS in anti-inflammation and repair. Many in vivo and in vitro basic studies have also reported the molecular effect mechanisms by which LIPUS exerts capacity of anti-inflammation and repair. This review focuses on the molecular mechanism of LIPUS anti-inflammation and repair and emphasizes the crucial role of LIPUS in various diseases. In addition, we compile clinical trials to provide readers with a more thorough understanding of the current potential of LIPUS in inflammation control and organ function restoration.

Background:There is limited information available on patients with asthma in hospitals in China. We investigated their clinical and phenotypic characteristics and management. Methods:The China Asthma Data Registry Project (CHART) study is a multicentre, hospital-based, prospective, observational study in which patients were recruited from outpatient clinics. This analysis used baseline cross-sectional data from patients with asthma (≥12 years) enrolled at 58 tertiary hospitals in China between 25 March 2018 and 11 July 2019. Results:A total of 20 683 patients with asthma (56.2% female, 15.0% patients with active tobacco use) were enrolled. Overall, 22.8% had uncontrolled asthma, 39.5% had partially controlled asthma. Furthermore, 45.3% experienced ≥1 exacerbation annually, including 31.7% who required hospitalisation, with only 21.4% having previously used inhaled corticosteroids (ICSs) in the past year. Cough (80.0%) was the most common symptom, followed by wheezing (70.7%), with 14.6% having cough-predominant asthma and 11.4% having cough-variant asthma. Multivariate logistic regression revealed that cough severity independently predicted poor control, irrespective of airflow limitation or inflammatory status. The association was stronger in ICS users than in nonusers across all cough severity metrics: a visual analogue scale (VAS) score ≥40 (aOR 3.88-5.47 versus 2.49-2.94), a cough evaluation test (CET) score ≥12 (aOR 11.15-20.91 versus 3.97-5.55), and a Leicester Cough Questionnaire (LCQ) score <15 (aOR 6.15-13.66 versus 2.45-3.18). Conclusions:We found significant suboptimal control, a high prevalence of cough-related phenotypes, frequent exacerbations and hospital admissions in patients with asthma attending hospitals. This underscores the need to prioritise the assessment and treatment of cough in asthma.

Idiopathic pulmonary fibrosis (IPF) is marked by excessive deposition of extracellular matrix (ECM) and persistent fibroblast activation in the lungs, posing challenges for advancing effective treatment strategies. Danthron, a natural anthraquinone derivative extracted from traditional Chinese medicine rhubarb, exhibits antitumor and antioxidant efficacy. A bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model and human precision-cut lung slices (hPCLSs) stimulated with a pro-fibrotic solution were employed. The therapeutic effects of danthron on PF were measured by histological manifestations, immunostaining and expression levels of fibrotic markers. Human fibroblasts (HFs) were utilized to explore the underlying mechanism of danthron on fibroblast function. Our data showed that danthron significantly mitigated BLM-induced PF by reducing collagen deposition and Ashcroft scores in mice. Danthron also suppressed the abundance of fibrotic markers in mouse lungs and hPCLSs. Additionally, danthron impeded the transition of lung fibroblasts to myofibroblasts while promoting their dedifferentiation. Mechanistically, the anti-fibrotic effect of danthron was associated with the upregulation of carboxylesterase 3 (CES3), which consequently enhanced mitochondrial function and mitophagy in fibroblasts. Pharmacological CES3 inhibition (WWL229) reversed these effects, whereas genetic CES3 overexpression potentiated its mitochondrial benefits. Moreover, WWL229 nullified the beneficial effects of danthron in BLM-induced PF. The downregulation of CES3 was identified in IPF patients, which exhibited a negative correlation with fibrotic genes. This study demonstrated danthron as a valuable experimental tool for identifying relevant targets in preclinical models while underscoring CES3 as a potential therapeutic target for PF.

Background: Biologics’ efficacy in relieving cough and dyspnea in severe eosinophilic asthma (SEA) is under-characterized. Objectives: This exploratory analysis evaluated the efficacy of benralizumab separately in reducing cough and/or dyspnea in patients with SEA. Design: Post-hoc analysis of a phase III, randomized, double-blind, placebo-controlled trial. Methods: MIRACLE (NCT03186209) data were used, involving patients aged 12–75 years with uncontrolled SEA. Patients reporting baseline frequent cough and/or dyspnea based on St George’s Respiratory Questionnaire (SGRQ) items were analyzed. Changes in cough frequency, cough-specific HRQoL, and dyspnea frequency measured through relevant SGRQ items were evaluated over 48 weeks. Subgroup analyses based on baseline blood eosinophil counts (bEOS ⩾300 cells/μL) were conducted. Results: A total of 383 patients (benralizumab: 189; placebo: 194) with baseline frequent cough and 304 with baseline frequent dyspnea (benralizumab: 151; placebo: 153) were included. The proportions of patients transitioning to non-frequent cough with benralizumab versus placebo were 54.0% versus 39.7% at Week 8 ( p = 0.0051), and 59.3% versus 56.7% at Week 48. Improvements in cough-related SGRQ items, including reductions in cough-related pain/fatigue, less sleep disturbance, and decreased embarrassment in public, occurred earlier with benralizumab compared to placebo and were sustained through Week 48. Among patients with higher inflammatory burden (baseline bEOS ⩾300 cells/μL), the prevalence of frequent cough at baseline was higher. In this subgroup, a higher proportion transitioned to non-frequent cough with benralizumab versus placebo at both Week 8 (55.3% vs 37.1%; p = 0.0027) and Week 48 (59.8% vs 52.1%). Differential improvements in cough-related SGRQ items favoring benralizumab were consistently observed. Reductions in dyspnea frequency followed a similar pattern, with benralizumab showing greater improvements versus placebo at both Week 8 (64.2% vs 47.1%; p = 0.0026) and Week 48 (75.5% vs 63.4%; p = 0.0221). Conclusion: Benralizumab showed potential to rapidly reduce cough and/or dyspnea frequency, and to improve cough-specific HRQoL more quickly than placebo in patients with SEA, with sustained advantage in cough-related SGRQ items through Week 48. Improvements were pronounced in patients with higher baseline bEOS, potentially reflecting a higher disease burden. However, as this was an exploratory analysis, further validation using cough-specific clinical endpoints is warranted. Trial registration: ClinicalTrials.gov, NCT03186209, https://clinicaltrials.gov/study/NCT03186209

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, and durable responses to current systemic therapies is still limited. Tumor-associated endothelial cells (TECs) actively shape the immunosuppressive tumor microenvironment and contribute to therapeutic resistance, yet they remain underexploited as therapeutic targets in HCC. Interleukin-13 receptor alpha 2 (IL-13Rα2), long regarded as a decoy receptor for IL-13, has recently emerged as a context‑dependent molecule with therapeutic relevance across several malignancies. In the liver, single-cell and spatial transcriptomic studies indicate that IL-13Rα2 is highly compartmentalized and enriched within endothelial populations, offering a new explanation for previously inconsistent expression data in HCC. In this review, we summarize IL-13Rα2 biology across chronic liver disease and HCC, discuss its compartment‑specific functions, and highlight key mechanistic and translational questions. We further propose a framework for aligning IL‑13Rα2‑targeted strategies with its spatial distribution within tumors, with particular emphasis on endothelial‑directed intervention. This perspective may expand therapeutic opportunities beyond the toxicity and resistance associated with current anti-angiogenic therapies.

The bidirectional communication between the liver and bone profoundly influences the development and progression of both liver and bone diseases and significantly affects systemic homeostasis. Through the metabolic and immune crosstalk mediated by hepatokines, osteokines, extracellular vesicles, gut microbiota, and neuroendocrine factors, the liver-bone axis not only affects the progression from chronic liver disease to liver cancer but also modulates the balance of bone formation and resorption as well as bone marrow homeostasis. Furthermore, a dysfunctional liver-bone axis can lead to systemic complications characterized by dyslipidemia and hyperglycemia. In this review, we discuss the pathophysiological changes induced by the dysregulated liver-bone axis and elucidate the specific mediating factors and mechanisms involved. We also summarize the current efforts in translating the liver-bone axis into clinical applications, aiming to provide potential therapeutic strategies for liver and bone diseases.

Protein lysine lactylation is a ubiquitous and post‑translational modification of lysine residues that involves the addition of a lactyl group on both histone and non‑histone proteins. This process plays a pivotal role in human health and disease and was first discovered in 2019. This epigenetic modification regulates gene transcription from chromatin or directly influences non‑histone proteins by modulating protein‑DNA/protein interactions, activity and stability. The dual functions of lactylation in both histone and non‑histone proteins establish it as a crucial mechanism involved in various cellular processes, such as cell proliferation, differentiation, immune and inflammatory responses and metabolism. Specific enzymes, referred to as 'writers' and 'erasers', catalyze the addition or removal of lactyl groups at designated lysine sites, thereby dynamically modulating lactylation through alterations in their enzymatic activities. The respiratory system has a remarkably intricate metabolic profile. Numerous pulmonary diseases feature an atypical transition towards glycolytic metabolism, which is linked to an overproduction of lactate, a possible substrate for lactylation. However, there has yet to be a comprehensive review elucidating the full impact of lactylation on the onset, progression and potential treatment of neoplastic and inflammatory pulmonary diseases. In the present review, an extensive overview of the discovery of lactylation and advancements in research on the existing lactylation sites were discussed. Furthermore, the review particularly investigated the potential roles and mechanisms of histone and non‑histone lactylation in various neoplastic and inflammatory pulmonary diseases, including non‑small cell lung cancers, malignant pleural effusion, pulmonary fibrosis, acute lung injury and asthma, to excavate the new therapeutic effects of post‑translational modification on various pulmonary diseases.

RNA viruses have evolved various strategies to bypass the mitochondrial antiviral-signaling protein (MAVS) pathway, effectively sidestepping the host's innate immunity. Therefore, searching for MAVS signalosome regulators is crucial for the development of antiviral drugs. Here, we found RNA viral-drived MAVS lysosomal trafficking was inhibited by Anemoside B4 (B4), a triterpenoid saponin from the herbal medicine Pulsatilla chinensis (Bunge) Regel., has significant antiviral activity. We performed biotin-B4 probe tandem proteomic profiling and identified ubiquitin fold modifier 1 (UFM1), one of the newly discovered Ub-like proteins (UBLs), as a key target of B4. Using cellular thermal shift assay (CETSA), surface plasmon resonance (SPR) analysis, and molecular docking analysis we showed that B4 directly bound to UFM1 through Lys34 and Ile57 sites and promoted UFMylation of target proteins. Furthermore, we found that MAVS UFMylation could promote polyubiquitination, K48- and K63-linked ubiquitination, yet preventing K27-linked ubiquitination. MAVS aggregation and innate immunity response were suppressed in virus infected UFM1 KO cells even in the presence of B4. Moreover, the decrease in K27-ubiquitin (Ub) binding on MAVS and lysosomal degradation induced by B4 was also significantly prevented by UFM1 deficiency. Importantly, to verify that MAVS UFMylation is the actual target for B4, cytoprotective and viral titer analysis were executed in cells lacking UFM1 challenged with Enterovirus 71 (EV71) and Influenza A virus (IAV). The findings uncover the new finding broad-spectrum antiviral mechanism of B4, suggesting that UFMylation of MAVS could be an advantageous approach for countering RNA viral infections.

Neutrophilic asthma, characterized by the relative accumulation of neutrophils in the airways, constitutes a distinct endotype of asthma resistant to corticosteroid and associated with severe and uncontrolled cases. Milk fat globule-EGF factor 8 (MFGE8) is a soluble glycoprotein functioning in phagocytosis, tissue repair, angiogenesis, and the regulation of neutrophil activity. However, the role of this glycoprotein in neutrophilic asthma has not been thoroughly investigated. MFGE8 concentrations were assessed in asthmatic patients with various endotypes. Utilizing an ovalbumin (OVA)/complete Freund’s adjuvant (CFA)-induced mouse model of neutrophilic asthma, we investigated the critical roles of MFGE8 in neutrophilic asthma in MFGE8-knockout (Mfge8−/−) mice by assessment of H E/PAS staining, bronchoalveolar lavage (BAL) cell counting, and lung function tests. Bioinformatic analyses were conducted to determine downstream functions, and mechanistic experiments were performed on primary cultures of neutrophils isolated from the mouse’s lungs. Recombinant MFGE8 was administered to the mice to evaluate its therapeutic effects. Our results demonstrated that MFGE8 is expressed in neutrophils, and its protein levels are significantly reduced in the sputum supernatant of patients suffering from neutrophilic and paucigranulocytic asthma. Mfge8−/− mice exacerbated airway neutrophil infiltration, mucus secretion, and hyperresponsiveness. Further mechanistic studies, involving gene sequencing of sputum cells and lung tissue biopsies of asthmatic patients from GEO databases, identified neutrophil extracellular traps (NETs) as the critical factor in the progression of neutrophilic asthma. MFGE8 was shown to inhibit the formation of NETs (NETosis) through interaction with integrin β3. The absence of MFGE8 or the application of integrin β3 inhibitor was found to enhance NETosis and promote the release of pro-inflammatory cytokines via NLRP3-Caspase-1 pathway. Upstream mechanism indicated that USP14 mediated the ubiquitination of MFGE8 and participated in the development of NETosis. Moreover, recombinant MFGE8 was observed to effectively mitigate neutrophilic airway inflammation. This study underscored the significance of the MFGE8/integrin β3 axis in ameliorating NETosis and neutrophilic airway inflammation, suggesting MFGE8 as a potential therapeutic target for neutrophilic asthma. Not applicable.

Hexokinase catalyzes the first rate-limiting step glycolysis. However, the roles of hexokinase 2 (HK2) in asthma remain incompletely understood. This study aimed to investigate metabolic alterations in asthma, focusing on the expression, function and regulation of HK2. In this study, non-targeted metabolomics analysis of 20 asthma patients and 15 healthy controls identified metabolic alterations in asthma, particularly in the glycolytic pathways. Consistently, HK2 expression was elevated in both asthma individuals and mice with allergic airway inflammation. Airway epithelium–specific HK2 knockdown and pharmacological inhibition with 2-deoxy-D-glucose (2-DG) significantly attenuated airway inflammation and hyperresponsiveness in mice induced by ovalbumin/ lipopolysaccharide. Mechanistic analyses demonstrated that HK2 regulates epithelial apoptosis and inflammation via interaction with peptidylprolyl isomerase F (PPIF), independent of voltage-dependent anion channel 1 (VDAC1). Asthma is associated with metabolic reprogramming, characterized by alterations in lipid and glucose metabolism. These findings establish HK2 plays a crucial role in asthma pathogenesis by promoting airway epithelial apoptosis and inflammation in asthma, suggesting its potential as a therapeutic target.

593 Background: Advanced metastatic ICC, characterized by poor survival and limited therapeutic options, may benefit from the combined use of surufatinib—a selective tyrosine kinase inhibitor targeting VEGFR 1, 2, and 3, FGFR1, and CSF-1R—and ICIs, alongside locoregional treatments like TACE, DEB-TACE, and HAIC. Methods: Eligible pts who were 18 -75 years old with histologically confirmed unresectable or metastatic intrahepatic cholangiocarcinoma were enrolled. Pts received surufatinib (250mg, orally daily), ICI, and locoregional therapies until surgery, disease progression, death, intolerable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), conversion to surgical resection rate and safety. Results: By July 31, 2024, 20 pts were enrolled and 10 pts were evaluated. Median age was 56.4 years (range: 36-69), with a majority being male (70%). 9 pts were pathologically confirmed as adenocarcinoma, 1patient was small bile tract type. Treatment included DEB-TACE (20%), TACE (30%), and HAIC (50%). 50% (5/10) pts achieved partial response (PR), 20% (2/10) pts accepted conversion surgery, 30% (3/10) pts achieved stable disease (SD), and the confirmed ORR was 50%, DCR was 80%. The median PFS (95%Cl: 6.9-NA months) had not yet matured, with no significant differences in survival benefits based on age or gender, though TACE showed potential benefits. The most common AEs of all grades were nausea (30%), dizziness (30%), and headache (10%), No grade ≥ 3 TEAEs or new safety signals occurred. Conclusions: Surufatinib plus immune checkpoint inhibitor, along with locoregional therapies showed preliminary anti-tumor activity and manageable toxicity for the 1L treatment of ICC, providing an additional treatment option for pts with ICC. Clinical trial information: NCT05236699 .

Severe asthma exhibits heterogeneity in airflow obstruction, driven by airway remodeling and air trapping, which can be noninvasively assessed via quantitative computed tomography (qCT). This study aimed to identify asthma phenotypes by clustering qCT measurements of airway dimensions, lung volumes, and densitometry, and to elucidate the underlying molecular pathways through sputum proteomics. We applied consensus clustering to qCT data from 239 asthma patients (severe and mild/moderate) and 68 healthy controls from the Chinese C-BIOPRED cohort. Four distinct qCT clusters emerged: cluster 1, characterized by luminal dilation, severe air trapping, and reduced lung density; cluster 2, with thickened airway walls and luminal narrowing without air trapping; cluster 3, showing mild luminal dilation, preserved lung volumes, and optimal spirometry; and cluster 4, featuring airway wall thickening, luminal narrowing, severe air trapping, and profound airflow obstruction. Sputum eosinophilia was elevated in clusters 1 and 4. Proteomics revealed upregulated pathways in apoptosis execution and cornified envelope formation in cluster 1, while clusters 2 and 4 exhibited enhanced complement activation, fibrin formation, plasma lipoprotein assembly, and insulin-like growth factor (IGF) transport regulation. These findings delineate qCT-derived phenotypes and their associated underlying mechanisms of airway remodeling and airflow obstruction in severe asthma.

Background Type 2 inflammation is a key inflammatory endotype of chronic obstructive pulmonary disease (COPD). The precise identification and targeted intervention of treatable traits related to type 2 inflammation are crucial directions in the current management of COPD. Recently, a growing body of evidence-based medical data has accumulated regarding the clinical characteristics, biomarkers, therapeutic agents, and efficacy evaluation of type 2 inflammation in COPD, providing strong support for clinical diagnosis and treatment. This clinical practice recommendation systematically reviewed the evidence-based medical literature and integrated clinical experience to present expert opinions, aiming to standardize and improve the management of type 2 inflammation in COPD. Methods This clinical practice recommendation followed Appraisal of Guidelines for Research and Evaluation II (AGREE II) and the Reporting Items for Practice Guidelines in HealThcare (RIGHT) statement to ensure the thoroughness and transparency. Clinical questions were primarily derived from surveys among experts in the field and thorough discussion at meetings. The evidence grading levels and recommendation grades adopted in the clinical practice recommendation follow the evidence grading levels and recommendation grades established by the Oxford Centre for Evidence-Based Medicine. The expert opinions were formulated through open discussion and expert voting. Expert opinions with an agreement rate of 80 % or higher among the experts are incorporated in the clinical practice recommendation. Results Eight clinical questions concerning diagnosis and treatment were proposed after expert discussion. In addition, fifteen specific major points of expert opinions about type 2 inflammation in COPD, involving clinical features, biomarkers, correlation with clinical outcomes, inhaled corticosteroid (ICS) treatment, biologic treatment and treatment response, were determined. Conclusions A set of comprehensive clinical practice recommendations focusing on the treatable trait of type 2 inflammation in COPD was established, which may provide potential guidance for the precision management of COPD.