Secondary S. aureus infection following influenza is a critical complication with limited therapeutic options and leading to high mortality. This study investigates the potential application of erucic acid against post-influenza S. aureus infection. Our findings reveal that erucic acid demonstrated protective efficacy, as reduced lung index, weight loss, and relieved lung damage with post-influenza secondary S. aureus infection in mice. Erucic acid significantly inhibited the increase of S. aureus adhesion mediated by PR8 infection in vitro and in vivo. VCAM-1 and CEACAM-1 were identified as key adhesion molecules mediating erucic acid's anti-adhesive effects through RNA-seq, molecular docking, and molecular dynamics simulations. Immunohistochemistry, qPCR, and WB were performed to validate erucic acid's regulatory effect on VCAM-1 and CEACAM-1. Although both VCAM-1 and CEACAM-1 overexpression in mouse lungs promoted S. aureus adhesion, paradoxically, only VCAM-1 overexpression in vitro enhanced bacterial adhesion to BEAS-2B cells. Moreover, erucic acid treatment markedly attenuated this effect by suppressing VCAM-1 overexpression. 16S rRNA sequencing exhibited that erucic acid administration alleviates gut dysbiosis mediated by secondary S. aureus infection post-influenza. These findings reveal that erucic acid attenuated S. aureus adhesion by suppressing PR8-mediated upregulation of VCAM-1 and CEACAM-1. Furthermore, it mitigated pulmonary injury and gut dysbiosis induced by post-influenza secondary S. aureus infection. These findings are expected to offer novel therapeutic strategies for secondary S. aureus infection post-influenza.

This study addresses the 2025 Chikungunya outbreak in Foshan City, Guangdong Province, China, by constructing a dual-model framework based on Ordinary Differential Equations (ODE) and Petri Nets (PN) for comparative analysis of Chikungunya transmission dynamics and reproduction number estimation methods. The research employs SEICR (Susceptible-Exposed-Infectious-Chronic-Recovered) compartmental modeling to compare two formal representations under matched epidemiological assumptions, and evaluates the timing of epidemic control measures through a three-phase intervention fitting protocol. Model validation results show that both models achieve root mean square errors (RMSE) of 30.98 (ODE) and 31.05 (PN), mean absolute errors (MAE) of 15.57 and 15.78, and R^2 = 0.9500 and 0.9498, respectively. Both models predict epidemic peaks at day 33 (406 cases), occurring 3 days earlier than the observed peak (432 cases), with a peak value error of 6.0

BackgroundHypercytokinemia is a major contributor of tissue damage and mortality in severe influenza. However, most studies rely on static, single-time-point measurements, providing limited insight into the evolving inflammatory response. The prognostic relevance of longitudinal cytokine trajectories remains poorly defined.MethodsWe conducted a multi-cohort analysis of 186 patients from three public datasets to identify cytokines with influenza-severity-dependent expression patterns. We then analyzed a longitudinal cohort of 33 patients with severe influenza who underwent serial cytokine measurements, using linear mixed-effects models to identify the top 10 severity-associated cytokines. Integrating both analyses, we defined a core cytokine panel and a composite core panel score. Prognostic value was assessed using time-varying Cox regression and landmark analyses, with comparisons against clinical predictors, including LODS scores and CRP, as well as sensitivity analyses adjusting for diabetes.ResultsA core panel of six pro-inflammatory cytokines (IL-8, IL-6, G-CSF, MCP-1, TNF-α, and MIP-1α) was identified. Non-survivors showed distinct longitudinal trajectories of the core panel score, characterized by a progressive increase over the disease course. Paired sputum analyses suggested that these systemic cytokine signatures partially reflected pulmonary inflammation. Baseline core panel scores were not significantly associated with mortality (HR 3.29, 95% CI 0.95-11.38; P = 0.059), whereas time-varying monitoring showed better model fit (AIC 29.34 vs 34.85). Core panel scores remained associated with mortality in analyses accounting for LODS scores, baseline CRP, and diabetes. Landmark analysis further suggested that updated core panel scores may provide increasing prognostic information over time compared with baseline assessment, with delta AUC increasing from near zero at day 5 to 0.24 by day 17 after ICU admission.ConclusionsDynamic monitoring of a core cytokine panel may provide greater prognostic information than single-time-point assessment in severe influenza, although these findings require validation in larger independent cohorts. Longitudinal inflammatory profiling may help refine risk stratification and provide a framework for future precision studies.

Background: Inactivated vaccines have been widely used in China and many low- and middle-income countries, but real-world evidence on the protective effectiveness of heterologous mRNA boosters after a SinoPharm primary regimen during Omicron waves in Chinese populations remains limited. This study aimed to evaluate the real-world infection protection effectiveness of a SinoPharm primary regimen with mRNA boosters during the 2022 Omicron (BF.7 and BA5.2 variants) wave in Macao, China. Methods: An online survey conducted for two days among Macao residents towards the end of the 2022 Omicron wave gathered 4,879 responses (61.7% female, n=3,010). Among the participants, 83.2% (n=4,052) reported receiving the SinoPharm primary vaccination regimen, while 20% (n=827) reported receiving mRNA boosters; 71.4% of respondents reported confirmed infections, with an average duration of 5.4 days testing positive. Logistic and Ordinary Least Squared regressions were utilized to analyze the infection risk and the number of days testing positive. Results: When compared to those who received a three-dose inactivated vaccine, those with one-dose mRNA booster shows a significantly lower likelihood of confirmed infection [odds ratio (OR) =0.421, P<0.01]. In the event of an infection, they also experienced a decreased likelihood of developing fever (OR =0.290, P<0.01), and fewer sick days (-0.931, P<0.05). Conclusions: Heterologous vaccination is recommendable for both the Chinese population and other low-to-middle-income countries that have predominantly adopted inactivated vaccines as their primary regimen. Future studies are needed to examine the long-term effects, which could not be assessed in this survey.

Coronavirus infections pose a significant threat to both human and animal health, causing widespread morbidity, mortality, and substantial economic losses. While vaccines are crucial for prevention, their efficacy is often limited by the high mutation rate of these viruses. This underscores the urgent need for anti-coronavirus drugs, particularly broad-spectrum antiviral agents. In this study, we demonstrated for the first time that Biochanin A (BCA), a bioactive isoflavonoid found in legumes, exhibits broad-spectrum antiviral activity against coronaviruses. BCA potently inhibits porcine epidemic diarrhea virus (PEDV), as well as human coronaviruses HCoV-OC43 and HCoV-229E in vitro, with EC50 values of 6.90, 2.80 and 15.4 μM, respectively. In a lethal mouse model of HCoV-OC43-induced encephalitis, oral administration of BCA (40–60 mg/kg) significantly improved animal survival and reduced cerebral viral loads. Mechanistic studies revealed that BCA upregulates the AMPK/Nrf2 signaling pathway, thereby increasing expression of the glutamate-cysteine ligase catalytic subunit (GCLC) and enhancing glutathione (GSH) biosynthesis. Our findings identify BCA as a promising host-directed antiviral agent and highlight its therapeutic potential against coronavirus infections.

Respiratory syncytial virus (RSV) remains a significant cause of serious lower respiratory tract infection, highlighting the urgent need for new antivirals. A series of amide bond containing fluorinated benzimidazole derivatives was synthesized, and substitution of the N-phenylcarboxamide moiety with five-membered heteroaryl groups led to enhanced potency, with 2- and 3-halogenated thiophene rings significantly improved anti-RSV activity. Structural optimization afforded compound 21, bearing a 3-bromo-N-phenylthiophene-2-carboxamide moiety, which exhibited subnanomolar potency against RSV (IC50 = 0.10 nM). Molecular docking studies suggest compound 21 forms stable hydrogen bonds and π-π stacking interactions with the pre-fusion F protein, providing a mechanistic basis for its activity. Compound 21 dose-dependently suppressed RSV F protein expression in HEp-2 cells and significantly reduced viral burden in the lungs in an RSV-infected murine model. These results identify compound 21 as a highly potent RSV fusion inhibitor and a promising lead for further antiviral development.

Objective:Wenyang Jiedu Granule (WYJD) is an effective traditional Chinese medicine (TCM) preparation that has been generally applied for treating respiratory infectious diseases. Clinical observations involving thousands of cases have demonstrated that WYJD could alleviate disease progression and improve symptoms in treating respiratory viral infections, including SARS-CoV-2 and influenza virus. However, the chemical basis and underlying mechanisms of WYJD against influenza A virus (IAV)-induced pneumonia remain to be elucidated. This study aimed to reveal the underlying mechanisms of WYJD in treating IAV-induced pneumonia by a combined strategy of network pharmacology, transcriptomics and experimental validation. Methods:The pneumonia model was established in BALB/c mice via infection with H1N1 IAV to evaluate the therapeutic effects of WYJD on IAV-induced pneumonia. Firstly, ultra-high performance liquid chromatography-quadrupole Exactive Orbitrap mass spectrometer/tandem mass spectrometer (UPLC-Q Exactive Orbitrap-MS/MS) was employed to analyze the main chemical components in WYJD-containing serum. Subsequently, the effects of WYJD on IAV-induced pneumonia were assessed through pathological observation, plaque forming assay, biochemical analysis, Evans blue staining assay, and immunofluorescence assay. Mechanistically, an integrated approach of network pharmacology and transcriptomics was applied to explore the potential active components, targets and related pathways of WYJD against IAV-induced pneumonia. Fluorescence TUNEL assay, quantitative real-time PCR (qRT-PCR) and Western blotting were utilized for experimental validation and mechanistic studies. Results:Using UPLC-Q Exactive Orbitrap-MS/MS, a total of 25 prototypes and 15 metabolites were identified in the serum of mice after WYJD administration. WYJD treatment showed protective effects on IAV-induced pneumonia by inhibiting inflammation and lung barrier damage in the IAV-induced pneumonia mice model. Network pharmacology combined with transcriptomics analysis indicated that WYJD exerted therapeutic effects against IAV-induced pneumonia mainly through the synergistic effects of 11 active components, which regulated ten critical signaling pathways via 86 targets. Further experimental validation demonstrated that WYJD could alleviate IAV-induced pneumonia via the IL-17 signaling pathway, Toll-like receptor 7‌ (TLR7)/Myeloid differentiation primary response dene 88 (MyD88)/mitogen-activated protein kinases (MAPKs)/activator protein 1 (AP-1) signaling pathway and apoptosis. Conclusion:This study revealed the main active components and mechanisms of WYJD against IAV-induced pneumonia through the IL-17 signaling pathway, TLR7/MyD88/MAPKs/AP-1 signaling pathway and apoptosis, which provides novel insights into the clinical application of WYJD in treating influenza and its complications.

Traditional Chinese medicine (TCM) has a long history of treating viral diseases through holistic approaches and multi-component formulations. In response to emerging global viral threats like coronavirus disease-2019 (COVID-19), TCM has demonstrated significant potential in both antiviral and immune-modulatory roles. This review summarizes the current state of TCM antiviral research, highlighting advances in identifying active components and elucidating their mechanisms, which include direct viral inhibition and immune regulation. Technological innovations, including artificial intelligence (AI)-driven drug discovery and advanced extraction methods, are accelerating the development of TCM antiviral products. However, challenges remain in standardization, mechanistic validation, and international regulatory acceptance. Looking ahead, research should prioritize systems pharmacology, the development of multi-dimensional evaluation models, standardized clinical trials, and global health integration. By addressing these challenges, TCM can play a vital role in worldwide antiviral strategies and public health.

Background:Fagopyrum acutatum is used in Chinese medicine for its heat-clearing, detoxifying and pus-expelling properties, particularly for respiratory diseases. However, the effect of Fagopyrum acutatum on inflammation induced by influenza A virus (IAV) remains unclear. This study aimed to assess how Fagopyrum acutatum extract (FAE) affected the inflammation underlying mechanisms of IAV in vitro and in vivo. Methods:The pharmacodynamic components in FAE were identified using ultrahigh-performance-liquid-chromatography (UPLC)-Q-Exactive mass spectrometry (MS). The mechanism of FAE was predicted through RNA sequencing (RNA-seq) analysis and confirmed via reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot. The protective effects of FAE on lung injury and systemic inflammation were evaluated based on survival rate, lung index, histopathological alterations in lung tissues, lung cytokine levels, leukocyte counts in peripheral blood and serum inflammatory factor levels. Results:There were 103 compounds (mainly carbohydrates and organic acids) identified in FAE. FAE reversed the IAV-induced expression of RIG-I, MDA5, TLR3, IP-10, IL-6, IL-8, IL-1β, TNF-α, and MCP-1 in A549 cells, and reduced NF-κB P65 and IKBα phosphorylation. In vivo, FAE improved survival rates, decreased lung index and alleviated pathological changes in lung tissue caused by IAV. Expression of MCP-1, TNF-α, IL-6, IP-10 in lung tissues of mice with influenza pneumonia decreased by FAE. In addition, FAE significantly improved H1N1-induced leukocyte alterations and serum cytokine levels. Conclusions:FAE effectively alleviates IAV-stimulated inflammation and lung damage via NF-κB signaling pathway.

Metabolic reprogramming is pivotal for modulating antitumor immunity of T cell. Here, we identify a distinct CD8+ T cell state, designated as pentose phosphate pathway (PPP)-enhanced effector T cell (Tpeec), which is induced by NQO1-mediated redox cycling. We demonstrate that lawsone (Law) serves as a specific NQO1 substrate. The Law-NQO1 axis elevates mitochondrial ROS through NADPH consumption, activating the AKT-FOXO1 signaling cascade to drive effector differentiation. Importantly, this redox-dependent process amplifies PPP activity, redistributing glucose flux to not only enhance mitochondrial fitness but also promote ribose-5-phosphate (R5P) accumulation, endowing Tpeecs with superior proliferative capacity and stemness. Consequently, Tpeecs exhibit robust antitumor efficacy, as validated both in vitro and in vivo. Our findings uncover a critical metabolic axis linking redox cycling to PPP-driven stemness in CD8+ T cells, thereby reconciling their effector function with long-term persistence. This discovery positions NQO1-bioactivatable agents as promising therapeutic tools for optimizing T cell immunotherapy.

BackgroundRespiratory syncytial virus (RSV) is a major cause of acute respiratory tract infections worldwide. The COVID-19 pandemic and associated non-pharmaceutical interventions (NPIs) substantially altered the transmission dynamics of respiratory viruses. However, post-pandemic changes in RSV epidemiology and their associations with meteorological factors remain insufficiently characterized in subtropical regions of China.MethodBased on 38,541 RSV test records collected in Guangdong Province from July 1, 2019 to July 2, 2023, the epidemic characteristics were analyzed across the pre-pandemic, pandemic, and post-pandemic phases. The shortest main epidemic period in each season was identified using a sliding window approach. Monthly percentage change was used to quantify temporal variations across epidemic seasons. Meteorological data were integrated to assess temporal trends and correlations. A Distributed Lag Non-linear Model (DLNM) was applied to quantify non-linear exposure–response relationships and lag effects of meteorological factors. An XGBoost model combined with SHAP was used for feature attribution and performance evaluation.ResultsRSV positivity rates exhibited pronounced seasonal and interannual variability throughout the study period. Epidemic periods ranged from 7 to 10 months and frequently extended beyond the traditional winter–spring season. Overall positivity rates increased from 8.19% in the pre-pandemic phase to 13.84% during the pandemic phase and 19.33% in the post-pandemic phase. Significant differences were primarily observed among children younger than 6 years. Multiple meteorological variables were associated with RSV activity. DLNM analyses identified non-linear threshold effects and short-term lag effects (0–3 weeks), with elevated RSV risk associated with specific ranges of temperature, dew point temperature, and precipitation. XGBoost models captured major temporal patterns in RSV activity, with lagged RSV indicators contributing most strongly to predictive performance, whereas meteorological variables provided modest incremental predictive value.ConclusionRSV activity in Guangdong during 2019–2023 was characterized by prolonged epidemic periods and altered seasonal patterns following the COVID-19 pandemic. Meteorological factors demonstrated non-linear and lagged associations with RSV activity, highlighting their potential role in shaping transmission dynamics. The combined DLNM and XGBoost-SHAP framework provided complementary insights into climate-related risk patterns and temporal forecasting of RSV activity. Continued surveillance and external validation are needed to determine whether the observed seasonal changes represent a stable long-term pattern and to improve the generalizability of predictive models.

INTRODUCTION:The differentiation in epidemic patterns and multiple influencing factors pose significant challenges to influenza forecasting, highlighting the need for novel methods to improve predictive accuracy and cross-regional generalizability. OBJECTIVES:This study aims to develop an adaptive feature selection model named AdaFluDR to address the time-varying nature of influenza transmission drivers across different periods and regions. METHODS:AdaFluDR integrates the SpaceTime and Crossformer models and utilizes a correlation-driven mechanism. This mechanism constructs a comprehensive score by integrating the temporal, frequency, and time domain information of features, and dynamically adjusts feature processing pathways based on this score. Subsequently, a multilayer perceptron (MLP) will be employed to model the nonlinear mapping relationship between the integrated features and the target variable for prediction generation. RESULTS:The AdaFluDR model outperforms traditional methods and other machine learning approaches, demonstrating robust predictive performance across multiple forecasting horizons (1-4 weeks), and strong generalization ability across the United States, Canada, and Portugal. CONCLUSION:Our study provides a novel and practical framework for forecasting influenza activity with reliable accuracy and cross-national applicability, providing a valuable tool for improving global epidemic preparedness and response strategies.

ETHNOPHARMACOLOGICAL RELEVANCE:Lianhua Qingwen (LHQW), as a classic compound formulation of traditional Chinese medicine, holds significant value in antiviral, anti-inflammatory, and immunomodulatory activities. AIM OF THE STUDY:This study aimed to systematically evaluate the anti-respiratory syncytial virus (RSV) activity of LHQW, elucidated its mechanisms of action, and identified its key active ingredients. MATERIALS AND METHODS:The antiviral effects were assessed using in vitro cell models and in vivo models of young and immunosuppressed mice. Network pharmacology was employed to screen potential active ingredients of LHQW. Molecular docking and surface plasmon resonance (SPR) were used to analyze the interaction between active ingredients and viral proteins. Changes in m6A modification and the expression of related enzymes were examined to explore epigenetic regulatory mechanisms. RESULTS:LHQW inhibited RSV replication in a dose-dependent manner, down-regulated the expression of inflammatory factors, and alleviated pulmonary pathological damage. These observations appeared to be associated with the potential suppression of the IKK-α/β-NF-κB pathway and the modulation of m6A modification homeostasis. Using network pharmacology, the component U17 was identified, and it appeared to exhibit significant anti-RSV activity both in vitro and in vivo. U17 was shown to interact with the RSV-F protein during early infection, which may contribute to blocking viral entry. CONCLUSIONS:LHQW may exert its anti-RSV effects partly through mechanisms associated with the suppression of the IKK-α/β-NF-κB pathway and the modulation of m6A epigenetic homeostasis. Notably, the constituent U17 emerges as a key active ingredient, which directly targets the RSV-F protein to block viral entry. These findings position U17 as a promising lead candidate for anti-RSV drug development and underscore the multi-target potential of traditional Chinese medicine in treating viral infections.

Ethnopharmacological relevance Sheng Jiangsan (SJS) authorized by the Chinese Food and Drug Administration for treating wind-heat common cold, exhibits broad-spectrum antiviral activity. However, its specific antiviral and anti-inflammatory mechanisms require clarification. Gut microbiota and their metabolites play significant roles in lung disease progression and intervention, yet no research has explored whether the anti-influenza effect of SJS-derived Qingjie-Tuire (QT) Granule involves these pathways. Aim of the study This study aimed to determine whether QT Granule exerts its anti-influenza effects through modulation of gut microbiota and metabolites, specifically investigating associated antiviral and anti-inflammatory mechanisms. An experimental study employing influenza-infected mice. Mechanistic analysis integrated 16S rRNA full-length sequencing, UHPLC-MS/MS metabolomics, fecal microbiota transplantation (FMT), and targeted probiotic intervention. Materials and methods Influenza-infected mice received QT Granule treatment. Gut microbiota composition was analyzed via full-length 16S rRNA sequencing. Metabolite profiles were assessed using UHPLC-MS/MS. Functional validation involved QT-treated mice FMT into infected mice and supplementing infected mice with Lactobacillus murinus and Lactobacillus reuteri (species enriched by QT). Outcomes included lung pathology, viral titers, survival, and lung/intestinal inflammation, and intestinal barrier integrity. Results QT treatment significantly reduced lung pathological damage, lowered viral titers, restored pulmonary macrophage and T-cell proportions, decreased p-STAT1/p-STAT3/p-ERK expression, maintained intestinal barrier function, attenuated lung and intestinal inflammation, and prolonged survival time/survival rate in infected mice. QT intervention restored influenza-depleted UFAs, including docosahexaenoic acid (DHA) and arachidonic acid (AA), and enriched L. murinus and L. reuteri. Crucially, both FMT using QT-treated mouse feces and direct supplementation with L.murinus/L. reuteri replicated QT's core therapeutic effects. Conclusions QT Granule exerts potent anti-influenza and anti-inflammatory effects by modulating gut microbiota (specifically enriching L.murinus and L.reuteri) and restoring UFA metabolites. This gut-lung axis mechanism provides novel insight into traditional Chinese medicine intervention in viral lung diseases.

Background Infection-induced acute lung injury (ALI) is a life-threatening clinical condition characterized by severe pulmonary inflammation. Lipopolysaccharide (LPS) is a core mediator of infectious acute pulmonary inflammation. Phillyrin (KD-1), a bioactive component of the traditional medicinal herb Forsythia suspensa, has therapeutic potential for acute pulmonary inflammation, but its mechanism remains unclear. The objective of this study was to investigate whether KD-1 attenuates inflammatory and ferroptosis-related responses in experimental acute lung injury, with potential involvement of JAK2/STAT1 signaling. Methods LPS-treated RAW264.7 macrophages and LPS-induced mouse models were used as experimental models. qPCR, flow cytometry, molecular docking, molecular dynamics simulations, Western blotting, transmission electron microscopy (TEM), and hematoxylin and eosin (HE) staining were performed to evaluate inflammatory and ferroptosis-related responses and the potential involvement of JAK2/STAT1 signaling. Results Phillyrin showed stronger binding to JAK2 than to STAT1 in docking, with best docking scores of −8.2 kcal/mol and −6.9 kcal/mol, respectively. Molecular dynamics simulations further indicated greater stability of the JAK2 complex, as reflected by lower complex RMSD, higher contact occupancy, and more favorable nonbonded interaction energy, providing computational support for a potential interaction between phillyrin and JAK2 rather than direct biochemical evidence. Functionally, phillyrin suppressed activation of JAK2/STAT1 signaling, significantly upregulated the expression of anti-ferroptotic molecules (GPX4, SLC3A2, and SLC7A11) (P < 0.05), and reduced the levels of pro-inflammatory and ferroptosis-related biomarkers (TNF-α, IL-6, NOX1, iNOS, ACSL4, and COX-2) (P < 0.05). These changes may be associated with reduced intracellular iron overload, attenuated reactive oxygen species (ROS) production and lipid peroxidation, together with alleviation of ferroptosis and excessive inflammatory responses in the LPS-induced pulmonary injury model. Conclusion Phillyrin showed a protective effect under pre-treatment conditions against ferroptosis- and inflammation-associated injury in an LPS-induced ALI model, with potential involvement of JAK2/STAT1 signaling. These findings support further investigation of phillyrin in experimental models of inflammation-associated lung injury.

Respiratory syncytial virus (RSV) is one of the leading causes of severe respiratory infections worldwide, particularly in pediatric and elderly populations. The RSV Fusion (F) protein, essential for viral entry and syncytium formation, represents a prime target for antiviral drug development. In this study, we constructed a compound class that contained saturated naphthene- and cyclic ether-fused pyrimidine bicyclic cores as potent Fusion inhibitors. Among these, the 5,6,7,8-tetrahydroquinazoline derivative 7d showed outstanding in vitro anti-RSV activity (RSV-long, EC50 = 3.65 ± 0.85 nM) and potent inhibition against multiple clinical isolates. Molecular docking, MD simulations, and MM-GBSA showed 7d tightly binds RSV pre-fusion F protein with strong affinity. 7d effectively inhibited RSV infection and syncytium formation in human nasal and airway organoids. The in vivo efficacy of 7d in reducing viral load and alleviating RSV-induced lung pathology was confirmed in both young and aged mouse models. By integrating in vitro, organoid, and in vivo models, this study validates compound 7d as a highly potent, lung-targeted RSV F protein inhibitor with promising therapeutic potential. These findings warrant further development of 7d as a novel antiviral candidate against RSV infection.

A growing body of evidence suggests that immune dysregulation plays a pivotal role in the pathogenesis of idiopathic pulmonary fibrosis (IPF); however, the precise regulatory mechanisms remain unclear. We aim to identify key inflammatory factors and immune cells that significantly contribute to the onset and progression of IPF, and to elucidate their specific mechanisms of action. The potential causal relationships between 731 immunocyte phenotype, 41 inflammatory cytokines and IPF were conducted using bidirectional two-sample Mendelian randomization (TwoSampleMR) analysis. The candidate targets were further screened in the peripheral blood of patients with IPF, as well as in both in vivo and in vitro models of pulmonary fibrosis (PF). In vitro experiments were performed by treating MRC5 cells with nerve growth factor (NGF) and the tropomyosin receptor kinase A (TRKA) inhibitor K-252a, or by transfecting the cells with siRNA targeting TRKA. Fibroblast activation was assessed using CCK-8 assays, wound healing assays, transwell migration assays, reverse transcription quantitative PCR (RT-qPCR), and western blot analysis. Additionally, co-immunoprecipitation (CoIP) was employed to verify the interaction between NGF and TRKA in MRC5 cells. In vivo studies examined the impact of NGF on immune responses and PF, as well as the antifibrotic effects of K-252a on these parameters. These evaluations were performed through histopathological examination, immunohistochemical analysis, immunofluorescence analysis, western blotting, and enzyme-linked immunosorbent assay (ELISA). The genetically predicted onset of IPF has been correlated with the expression of NGF, which is significantly upregulated in the peripheral blood of individuals diagnosed with IPF. Furthermore, genetic analyses have implicated the involvement of two distinct immune cell populations in the initiation of IPF, with a particularly strong association observed between CD4 on CD39+ regulatory T cells (Tregs) and the risk of developing IPF (odds ratio [OR] = 1.13, 95

Airborne transmission plays a central role in the spread of seasonal influenza; however, the determinants governing strain-specific airborne infectivity remain poorly understood. Here, we integrated exposure-infection assays with controlled bioaerosol chamber experiments to quantitatively resolve differences between influenza A and B viruses across aerosolization and aging processes. By coupling these measurements with an effective inhaled dose model, we enabled strain-resolved comparisons of exposure potential as a function of host age and activity level. Our results show that strain-dependent differences in aerosolization efficiency, hygroscopic behavior, virion morphology, and physical stability cannot fully account for variations in airborne infectivity. Instead, biological inactivation during aerosol aging emerges as a key factor governing the loss of infectivity in airborne particles. Accordingly, A/H3N2 maintains higher aerosol-phase infectivity across size ranges, whereas influenza B strains display more rapid loss of infectivity. Collectively, these findings identify aerosol-phase biological stability as a primary determinant of strain-specific airborne infectivity and provide a quantitative framework for assessing the aerosol exposure potential of emerging influenza variants and informing indoor respiratory health interventions.