The processes of pyroptosis, apoptosis, and necroptosis (PANoptosis) play a crucial role in the development of chronic obstructive pulmonary disease (COPD). Our objective is to explore potential PANoptosis-related genes in COPD.

Human COPD-related transcriptomic datasets (GSE8545, GSE20257, GSE11784 and GSE1650) were retrieved from the Gene Expression Omnibus (GEO). First, based on GSE8545 dataset, candidate genes were identified using differentially expressed gene (DEG) analysis, Weighted Gene Co-expression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO) regression, and Support Vector Machine-Recursive Feature Elimination (SVM-RFE). Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted for the relevant genes. CD14 was identified as a diagnostic biomarker through validation across independent human cohorts (GSE20257 and GSE11784). CIBERSORT was employed to evaluate immune infiltration differences between CD14 expression groups. Finally, potential therapeutic drugs for CD14 were predicted using the Drug-Gene Interaction Database (DGIdb).

Three PANoptosis-related hub genes (CD14, IRF2, and BOK) were defined in this study. KEGG enrichment analysis revealed that these genes were significantly enriched in the "Apoptosis - multiple species" signaling pathway. Validation across multiple independent human datasets identified CD14 as the key gene. CD14 exhibited significantly elevated expression in the lung tissues of COPD patients (P < 0.001). Immune infiltration analysis indicated that CD14 expression levels were significantly negatively correlated with resting mast cells and positively correlated with monocytes. Receiver Operating Characteristic curve analysis confirmed the robust diagnostic performance and stability of CD14, with Area Under the Curve values of 0.756, 0.702, 0.703, and 0.732 in the GSE8545, GSE20257, GSE11784, and GSE1650 datasets, respectively. Furthermore, three potential therapeutic agents targeting CD14-VB-201, LOVASTATIN, and IC143-were predicted.

We identified CD14 as a marker gene associating with PANoptosis in COPD, providing new ideas for clinical diagnosis and drug design of COPD.

Circular RNAs (circRNAs) constitute a recently identified class of non-coding RNAs that are widely distributed in eukaryotes. Characterized by the absence of 5' caps and 3' polyadenylated tails, circRNAs may regulate gene expression through multiple mechanisms. Recent studies have shown that certain circRNAs contain binding sites complementary to microRNAs (miRNAs), enabling them to function as molecular sponges that sequester miRNAs and inhibit their suppressive effects on mRNA expression. Emerging evidence indicates that specific circRNAs are involved in the regulation of immune cells and cytokines associated with type 2 chronic rhinosinusitis; however, direct clinical evidence supporting associations between circRNAs and the diagnosis or severity of type 2 chronic rhinosinusitis remains unavailable. In this study, the molecular mechanisms of circRNAs in type 2 inflammation are systematically summarized, established experimental evidence is distinguished from clinical applications that remain to be validated, and a theoretical basis is provided for future research on type 2 chronic rhinosinusitis.

Interferon-induced protein 27 (IFI27) is implicated in immune regulation, and regulatory T cells (Tregs) play a critical role in maintaining pulmonary immune homeostasis during sepsis. However, the relationship between IFI27 and Treg-mediated regulation in sepsis-associated lung injury remains unclear. This study aimed to investigate the role of IFI27 in modulating Treg function during sepsis.

Plasma IFI27 levels were measured in patients with sepsis and healthy controls. mRNA sequencing was performed to assess IFI27 expression profiles. In vivo, IFI27 expression was examined in a cecal ligation and puncture (CLP) mouse model, and an IFI27 overexpression mouse model was used to evaluate its functional role in sepsis. Immunofluorescence staining and transmission electron microscopy were employed to assess ferroptosis in lung epithelial cells. Flow cytometry was used to analyze Treg populations and their secretion of interleukin-10 (IL-10). In vitro, primary Tregs were co-cultured with mouse lung epithelial cells to determine the effects of IFI27 on IL-10 secretion in Tregs and epithelial ferroptosis. Reactive oxygen species (ROS) levels, malondialdehyde (MDA) content, and STAT3 pathway-related protein expression were quantified using ROS assays, MDA measurements, and western blotting, respectively.

Clinical analyses demonstrated that plasma IFI27 levels were positively correlated with sepsis severity. IFI27 expression was significantly increased in septic mice. Elevated IFI27 inhibited STAT5 phosphorylation, leading to a reduction in Treg abundance and IL-10 secretion, thereby exacerbating ferroptosis in pulmonary epithelial cells. Furthermore, IFI27 elevation in Tregs increased lipid peroxidation levels by suppressing the IL-10/STAT3 signaling pathway.

These findings indicate that IFI27 is closely associated with sepsis severity and may serve as a potential prognostic indicator. Mechanistically, IFI27 suppresses Treg function and enhances ferroptosis in lung epithelial cells through inhibition of the IL-10/STAT3 signaling pathway, thereby aggravating sepsis-induced lung injury.

Despite the role of booster doses in sustaining protection against emerging SARS-CoV-2 variants, global uptake remains low, highlighting the need for dose-sparing strategies that maintain durable immunity. We conducted a randomized controlled trial in Mongolian adults to examine long-term cellular immune responses to standard and fractional doses of BNT162b2 given as a third dose. A total of 601 participants, primed with ChAdOx1-S, BBIBP-CorV, or Gam-COVID-Vac, were randomized (1:1) to receive 15 μg (fractional dose) or 30 μg (standard dose) of BNT162b2. A subset of participants (N = 256) were enrolled for cell-mediated immunity analysis (n = 101 ChAdOx1-S primed, n = 117 BBIBP-CorV primed, n = 38 Gam-COVID-Vac primed). Antibodies were measured for binding anti-Spike IgG and neutralizing antibodies, and T-cell responses were measured using activation-induced marker (AIM), intracellular cytokine staining (ICS), and IFN-γ against SARS-CoV-2 Spike-specific wild-type and JN.1, and followed-up for 12 months. At 12 months post-vaccination, wild-type and JN.1 IgG levels were sustained and remained approximately 1.7-2.7-fold higher than baseline levels, and neutralizing antibodies were maintained (89% inhibition) for each priming stratum and standard and fractional dose groups. Across all study visits, total AIM CD4mem (expressing CD69+, OX40+, or CD137+) and CD8mem (CD69+CD137+), total ICS CD4mem and CD8mem (IL-2+, TNF-α+, or IFN-γ+), and ELISpot IFN-γ remained similar by study arm and priming strata for wild-type and JN.1 responses. CD4mem AIM responses peaked 6 months post-vaccination; by 12 months, responses to wild-type were maintained, whereas JN.1 responses had declined to day 28 levels or lower. For memory T-cell ICS responses, durability was maintained over 12 months post-vaccination for both wild-type and JN.1 responses. Overall, fractional booster dosing produced comparable and robust long-term humoral and cellular immune responses to a standard dose, including against the JN.1 variant.

Accurate diagnosis of existing and emerging respiratory pathogens is important. We evaluated the capability of unbiased metagenomic next generation sequencing (mNGS) to identify pathogenic RNA viruses from two cohorts of nasopharyngeal (NP) swabs previously tested by commercial multiplex respiratory diagnostics.

NP swabs (N = 100) in viral transport media (VTM) were assessed using mNGS for this study. Cohort 1 (N = 52) consisted of symptomatic individuals who tested negative for SARS-CoV-2, influenza A/B, and RSV by the Xpert Xpress CoV-2/Flu/RSV Plus multiplex respiratory virus panel and were tested by mNGS for undetected pathogens. Cohort 2 (N = 48) included symptomatic individuals who were positive (N = 26) or negative (N = 22) by the ePlex RP2 multiplex respiratory pathogen panel. Samples were positive for influenza A (N = 8), rhinovirus/enterovirus (N = 5), RSV (N = 4), adenovirus (N = 3), parainfluenza (N = 2), seasonal coronaviruses (N = 2), and human metapneumovirus (N = 1), as well as a rhinovirus/enterovirus/human metapneumovirus co-infected sample (N = 1). mNGS results were compared with ePlex RP2 findings, and symptomatic negative samples were evaluated for additional pathogen detection.

Cohort 1 contained 8% (4/52) viral and 19% (10/52) bacterial reads. In cohort 2, positive concordance between ePlex RP2 and mNGS was 31% (8/26). mNGS did not identify any viral reads in ePlex RP2-negative samples. However, it detected other microbial reads, such as Acanthamoeba castellanii, in 21% (10/48) of samples.

In this study, targeted multiplex amplification methods demonstrated better overall sensitivity in NPs of symptomatic respiratory individuals than mNGS. Other mNGS approaches may produce different results. This study suggests that mNGS may offer adjunctive information, including the detection of rare pathogens, which may be helpful in some clinical contexts.

The oxygen-rich milieu of the lungs necessitates precise iron homeostasis and regulation, processes that are fundamental to pulmonary physiology but often receive limited attention. However, in recent years, dysregulation of iron homeostasis has been linked to numerous acute and chronic respiratory diseases. Here, we comprehensively evaluate the mechanisms governing iron homeostasis in the alveolar epithelium of the lung and examine how iron dysregulation contributes to impaired alveolar epithelial repair in respiratory disease. This Review focuses on the effects of iron on alveolar epithelial cell homeostasis and repair and disease pathogenesis. There will be a focus on emerging interventions designed to reestablish iron homeostasis and their potential therapeutic implications related to enhancing lung repair and limiting the progression of lung disease.

Lung IL-33 is involved in pathogen defense, barrier homeostasis, and development of allergic responses. We previously identified a 5 kb noncoding region within a GWAS-defined segment that regulates expression of human IL33 (hIL33) but is absent in the murine locus. To understand how this region affects IL-33 expression in vivo, we engineered 2 BAC-transgenic strains in which 166 kb of the human genome upstream of the hIL33 locus, along with a fluorescent reporter, was inserted into the murine genome, both with and without the 5 kb region. Comparison to a murine Il33 (mIl33) reporter strain revealed species-specific tropism; hIL33 reporter was mostly expressed in the endothelium, while mIl33 reporter was expressed in type 2 alveolar epithelium. hIL33 reporter expression in tracheal basal epithelium, submucosal glands, and lung microvasculature required the 5 kb region. Surprisingly, allergen and exogenous IL-33 downregulated hIL33 reporter in lung endothelium only when the 5 kb region was present. Similar IL-33-dependent downregulation of IL33 transcripts was observed in human endothelial cell lines, validating that our hIL33 reporter strain recapitulated human endothelial biology. Together, these data reveal the importance of the asthma-associated human 5 kb region in regulating human IL33 expression in a cell type- and context-dependent manner.

Enhancers play an important role in transcriptional regulation by modulating gene expression from distal genomic locations. Although single-cell ATAC and RNA sequencing (scATAC/RNA-seq) data have been leveraged to infer enhancer-gene links, establishing regulatory links between enhancers and their target genes remains a challenge due to the absence of chromatin conformation information. Here, we present SCEG-HiC, a machine learning method based on weighted graphical lasso, which decodes enhancer-gene links from single-cell multi-omics data by integrating bulk average Hi-C as prior knowledge. SCEG-HiC supports both paired scATAC/RNA-seq and scATAC-only inputs, improving prediction accuracy while retaining context-specific correlations and enabling the discovery of biologically relevant links. Comprehensive evaluation across 10 human and mouse single-cell multi-omics datasets shows that SCEG-HiC outperforms existing single-cell models. Application of SCEG-HiC to COVID-19 datasets illustrates its capacity to more reliably reconstruct gene regulatory networks underlying disease severity, and elucidate functional associations between noncoding variants and their putative target genes. SCEG-HiC is freely available as an open-source and user-friendly R package, facilitating broad applications in regulatory genomics research.

BackgroundSepsis and its complications pose a major global health burden. Mendelian randomization (MR) provides a genetic approach to assess causality.MethodsWe conducted a two-sample Mendelian randomization (MR) study using data from large-scale genome-wide association studies (GWAS). This study aimed to assess the causal effects of six key biomarkers (D-dimer, Galectin-3, activated protein C, tumor necrosis factor receptor 2, interleukin-6 receptor subunit alpha, and thrombomodulin) on six sepsis-related complications, including acute respiratory distress syndrome (ARDS) and acute renal failure. The primary analysis utilized the inverse-variance weighted (IVW) method, with comprehensive sensitivity analyses to assess for heterogeneity and pleiotropy. A False Discovery Rate (FDR) was applied to correct for multiple testing.ResultsThe primary IVW analysis suggested several potential causal associations. Genetically predicted D-dimer was associated with a lower risk of ARDS (OR = 0.63, P = 0.025), IL-6Rα with a reduced risk of acute renal failure (OR = 0.85, P = 0.035), and Galectin-3 with a lower risk of streptococcal septicaemia (OR = 0.95, P = 0.039). Reverse MR analysis suggested that genetic liability to sepsis (critical care) was associated with lower D-dimer levels. However, after FDR correction, none of these associations remained statistically significant. Sensitivity analyses did not indicate the presence of significant horizontal pleiotropy.ConclusionThis study did not find robust genetic evidence to support a causal relationship between the six selected biomarkers and the risk of sepsis-related complications after correction for multiple testing. The suggestive associations observed prior to correction warrant further investigation.

Heart failure (HF) with mildly reduced ejection fraction (HFmrEF) or preserved EF (HFpEF) constitutes 74% of all HF cases in the US and is associated with significant clinical and economic burdens. Hospitalizations for HFmrEF/HFpEF are a leading contributor to the rising economic burden of HF. This literature review aims to identify key drivers of hospitalization costs for patients with HFmrEF/HFpEF in the US and to inform targeted interventions to reduce health care expenditures.

A comprehensive search of MEDLINE and Embase was conducted to identify observational studies published between January 2022 and May 2025 that reported on hospitalization-related costs for US adults with HFmrEF/HFpEF (defined as left ventricular ejection fraction ≥ 40%). Eligible studies were those reporting direct costs of hospitalization, readmission rates, time to readmission, length of stay, and number of hospitalizations per person. Data were synthesized narratively, and costs were adjusted to 2025 US$.

Of 2624 records identified by the literature searches, 37 studies met inclusion criteria. Total annual costs for HFmrEF/HFpEF were $36,921 to $49,081 per person per year (PPPY), with inpatient hospitalizations accounting for nearly half ($18,844-$20,095 PPPY). Readmissions were a major cost driver, with median all-cause readmission costs ($21,371-$28,615) consistently higher than index admission costs ($13,763-$14,944). Approximately 20% of patients were readmitted within 30 days, with HF-specific readmissions accounting for one-third of 30-day readmissions. Comorbidities such as type 2 diabetes (T2D) and chronic kidney disease (CKD) significantly increased costs, with patients having multiple morbidities incurring nearly double the costs of individuals without comorbidities. Prolonged hospital stay was also linked to higher costs.

HFmrEF/HFpEF hospitalizations represent a significant economic burden that is driven by high inpatient costs, frequent readmissions, and coexisting conditions (eg, T2D, CKD). These findings highlight the need for improved adherence to guideline-directed medical therapy and better management of comorbidities. Policymakers and health care providers should prioritize strategies to reduce HF-related hospitalizations and readmissions to mitigate the growing economic impact of HF.