Long-term abuse of methamphetamine (MA) is strongly associated with severe lung injury. Microbiome metabolites are one way to understand the interactions between microbes and disease. Although gut microbes and their metabolites play a crucial role in the gut–lung axis, the microbial mechanism by which MA induces lung injury is unclear. The purpose of this work was to identify the omics characteristic factor associated with MA abuse and explore its immune regulatory mechanism by 16 s rDNA sequencing, LC–MS/MS non-targeted metabolomics analysis, hemodynamics, flow cytometry, and some methods of cellular and molecular biology and morphology. Based on the joint analysis of the gut microbiome and metabolomics, it was found that MA abuse disrupted the structure of the gut microbiome and drove the reprogramming of metabolites, leading to a reduction in Lactobacillus rhamnosus and its metabolite L-kynurenine (L-KYN). Activated Lactobacillus increased L-KYN level in MA-administrated mice. L-KYN, as a product of Lactobacillus, is a key omics signature factor for MA abuse, which has been further confirmed in vivo. L-KYN induced Treg cells differentiated from CD4+ T cells and reshaped the immune microenvironment. L-KYN induced the secretion of IL-10 by Treg cells, mediated the communication between Treg cells and alveolar epithelial cells (AEC) through IL-10, and alleviated MA-induced lung inflammation and alveolar barrier damage through the IL-10/JAK1/STAT3 pathway. From the perspective of intestinal microbiome–metabolite–immune network regulation, the omics characteristic factor L-KYN reshaped the immune microenvironment and alleviated methamphetamine-induced chronic lung injury through the gut–lung axis, providing a new theoretical and experimental basis for the prevention and treatment of MA-induced chronic lung injury.

This study explores the impact of gut microbiota-derived metabolites on the pathogenesis of bronchopulmonary dysplasia (BPD), focusing on their roles in macrophage plasticity and inflammation. In a prospective nested case-control cohort of 30 infants with BPD and 33 preterm controls, 16S ribosomal RNA (16S rRNA) and mass spectrometry analyses identified seven differential gut bacterial genera, with depleted Streptococcus and enriched Klebsiella in patients with BPD, alongside reduced fecal and serum cholic acid levels. In chorioamnionitis-induced rat models of BPD, cholic acid supplementation alleviated lung inflammation by regulating macrophage migration and polarization. RNA-sequencing and in vitro experiments revealed that cholic acid acts by inhibiting hypoxia-inducible factor-1α (HIF-1α) expression and transcriptional activity, an effect that was abolished by HIF-1α silencing. These findings connect the gut microbiota to BPD, highlighting cholic acid as a key regulator of macrophage function through the HIF-1α pathway in mitigating inflammation and providing new clues for understanding and intervening in BPD.

The global aging population has increased the burden of cardiovascular and cerebrovascular diseases, which remain leading causes of morbidity and mortality worldwide. In their pathogenesis, platelets not only promote thrombus formation but also exert proinflammatory effects that cause extensive inflammatory responses, accelerating atherosclerosis and endothelial dysfunction. Traditional systemic anti-platelet agents face considerable challenges in elderly patients due to the delicate balance between antithrombotic efficacy and bleeding risk. Polymeric anti-platelet carriers alter the risk-benefit balance between antithrombotic efficacy and bleeding complications through local, biomarker-guided drug delivery. This review systematically summarizes platelet dysfunction in age-related cardiovascular and cerebrovascular diseases and corresponding strategies for constructing precision-targeted polymeric carriers. We first summarize major platelet-related biomarkers that have emerged as actionable targets, including glycoprotein VI (GPVI), platelet-derived growth factor-B (PDGF-B) and its receptor PDGFR-β, reactive oxygen species (ROS), and disease-associated shear stress. We then review recent advances in surface engineering approaches for targeted delivery, with emphasis on ligand-guided targeting, biomimetic cloaking, and multivalent binding designs. Next, we discuss carrier architectures tailored to improve drug loading and enable controlled release, highlighting stimuli-responsive platforms that exploit thrombotic microenvironmental signals, such as acidic pH, enzyme enrichment, oxidative stress, and shear forces, to trigger site-specific drug liberation. We also outline synergistic strategies that integrate anti-inflammatory and thrombolytic actions with biomimetic features to more effectively manage cardiovascular and cerebrovascular disorders. Finally, we consider future opportunities for polymeric anti-platelet delivery systems, focusing on materials innovation, patient stratification and personalization, and translational considerations that will shape long-term clinical utility. Overall, this review underscores the promise of polymer-based anti-platelet carriers for the prevention and treatment of age-related cardiovascular and cerebrovascular diseases.

Abstract Maternal diabetes during pregnancy increases the risk of metabolic and cardiac disorders in offspring. Nevertheless, the mechanism by which intrauterine hyperglycemia affects neonatal cardiac remodeling remains uncertain. This study aims to characterize the prenatal environment in the context of gestational diabetes mellitus and to identify the corresponding fetal changes. Using an intrauterine hyperglycemia rodent model, we observe cardiac remodeling and inflammatory responses in offspring hearts. Moreover, the O -GlcNAcylation levels are increased in neonatal hearts exposed to gestational diabetes. Further mechanistic investigations, supported by RNA sequencing and mitochondrial functional analyses, reveal that gestational diabetes triggers O -GlcNAcylation-dependent activation of CaMKIIδ during the embryonic stage. This activation leads to the release of mitochondrial DNA (mtDNA) from the mitochondrial matrix into the cytosol, which subsequently activates STING signaling and triggers an inflammatory response in neonatal cardiomyocytes. Pharmacological or genetic inhibition of O -GlcNAcylation attenuates mtDNA-induced myocardial inflammation and improves cardiac function in neonatal offspring subjected to intrauterine hyperglycemia. Together, these findings identify a previously unrecognized CaMKIIδ/mtDNA/STING axis in which CaMKIIδ O -GlcNAcylation leads to mtDNA-dependent activation of cardiac remodeling, suggesting that plasma mtDNA levels could serve as a predictive biomarker in neonatal cardiac inflammatory injury.

BACKGROUND AND AIMS:Atherosclerosis (AS) and abdominal aortic aneurysm (AAA) are both metabolism-associated vascular diseases, yet the role of lipid metabolic disturbances in their pathogenesis remains largely unknown. This study aimed to clarify the differential impact of lipid metabolic disturbances and their underlying mechanisms in AS and AAA. METHODS:Lipidomic analysis was performed to identify lipid metabolic differences between AS and AAA in various mouse models and different human cohorts. A multi-omics approach, integrated with functional assays, was utilized to elucidate the downstream mechanisms underlying disease-specific lipid metabolic features. Machine learning models were developed based on lipidomic features to differentiate AS from AAA. RESULTS:Lipidomic analysis of mouse models and human samples revealed a predominant enrichment of neutral lipids (e.g. triglycerides and cholesterol esters) in AS, in contrast to phosphoglycerides in AAA. Consistently, large-scale longitudinal data from the UK Biobank showed strong positive associations of triglycerides, cholesterol, and fatty acid with the future risk of coronary atherosclerotic disease, while phosphoglycerides were negatively associated with the risk of AAA. Integrated transcriptomic and metabolomic analyses identified fatty acid metabolism, particularly Acadm-mediated fatty acid β-oxidation (FAO) pathway, as the most significantly altered lipid metabolic pathway contributing to the lipid metabolic differences between AS and AAA. Consistently, targeted restoration of the Acadm-mediated FAO pathway inhibited AS by reducing lipotoxic metabolites and preserving mitochondrial homeostasis but had little impact on AAA. Further validation with lipid droplets autophagy-tethering compound (LD·ATTEC), which selectively eliminates intracellular lipid droplets, significantly alleviated AS progression and improved FAO with no significant change observed in AAA. Finally, predictive models were developed based on lipidomic features using machine learning algorithms, facilitating accurate differentiation between these two vascular diseases. CONCLUSIONS:These findings define previously unrecognized distinct lipid metabolic characteristics in the pathogenesis of AS vs AAA, providing a basis for differential diagnosis and targeted treatments.

Oxidized low-density lipoprotein (oxLDL) is a central driver of inflammatory responses in atherosclerosis and triggers multiple forms of regulated cell death beyond classical apoptosis. Ferroptosis, characterized by iron-dependent lipid peroxidation (LPO), and pyroptosis, mediated by inflammasome-activated gasdermin D (GSDMD) pore formation, have emerged as critical contributors to plaque progression and instability. Recent evidence highlights a significant crosstalk between these two death modalities: the N-terminal fragment of GSDMD targets mitochondrial membranes to promote LPO, while ferroptotic byproducts—including oxidized phospholipids and 4-hydroxynonenal—activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. This bidirectional interplay establishes a positive feedback loop that amplifies vascular inflammation. This review summarizes the molecular mechanisms underlying oxLDL-induced ferroptosis and pyroptosis, emphasizes their interconnected regulatory networks, and discusses therapeutic strategies targeting this cell death axis. Understanding this integrated cell death network may provide new insights for resolving residual inflammatory risk in atherosclerotic cardiovascular disease.

[This corrects the article DOI: 10.1016/j.isci.2026.115398.].

Adequate vitamin D is essential for the health of both the mother and fetus, and it can be influenced by environmental factors. However, research on the associations between greenness exposure and vitamin D concentrations during pregnancy is limited. This retrospective birth cohort study, conducted from 2014 to 2018, assessed the greenness of residences using the satellite-derived normalised difference vegetation index (NDVI). Serum 25-hydroxyvitamin D [25(OH)D] concentrations were categorised as non-deficient (≥50 nmol/L) or deficient (<50 nmol/L). Multiple log-binomial regression models were used to estimate the association of NDVI with serum 25(OH)D concentrations and vitamin D deficiency (VDD). Subgroup and mediation analyses were conducted to estimate the association of ambient particulate matter (PM) on the association between NDVI and VDD. A total of 64,663 pregnant women with a mean maternal age of 30.6 (standard deviation: 3.86) years were included. 250-m NDVI was negatively associated with the risk of VDD (per 0.1-unit increase, relative risk [RR]: 0.98, 95 % CI: 0.97-0.99). With the highest quartile of NDVI exposure as the reference group, the upper-middle quartile (RR: 1.02, 95 % CI: 1.00-1.03), and lowest quartile (RR: 1.03, 95 % CI: 1.01-1.06) had an increased risk of VDD. At higher PM2.5 exposure concentrations, 250-m NDVI exposure was negatively associated with the risk of VDD (RR: 0.98, 95 %CI: 0.97-0.99, per 0.1-unit increase), but not at lower PM2.5 exposure concentrations. Among pregnant women with higher PM2.5, the mediation of PM2.5 exposure on the association between 250-m NDVI and VDD was 44.70 % (P = 0.0116). Among pregnant women with higher PM10 exposure, the mediation of PM10 exposure on the association between 250-m NDVI and VDD was 17.98 % (P = 0.002). These findings suggest that higher residential greenery significantly reduces the risk of VDD in pregnant women, particularly in those exposed to increased PM concentrations.

OBJECTIVE:Hundreds of countries have implemented lockdown policies to slow the spread of coronavirus disease-2019 (COVID-19), but the impact of these measures on maternal mental health is not well understood. METHODS:This study integrated a stress-process model to examine the pathways from lockdown-related stressors to prenatal psychological outcomes, with COVID-19 coping strategies (COP) and self-efficacy in managing negative affect (NEG) as mediators and lockdown duration, hours on pandemic-related information, and number of pregnancies as moderators. Pregnant women in Shanghai completed the Regulatory Emotional Self-Efficacy Scale, COVID-19 Coping Scale, Depression, Anxiety, and Stress Scale-21. Structural equation modeling (SEM) was used to test and modify the hypothetical model, and moderated mediation and slope analyses were undertaken. RESULTS:In the final SEM demonstrating satisfactory fit, three stressors-decreased household income, insufficient daily supplies, and acquired infections-showed positive direct relationships with NEG and COP. Acquired infections, NEG, and COP were identified as direct predictors of mental health outcomes. The relationship between these three stressors and mental health was mediated by NEG and COP. Additionally, the number of pregnancies moderated the mediating effect of COP; this effect was more pronounced among first-time pregnant women than those with multiple pregnancies. CONCLUSION:This study provides insights into how lockdown measures impact psychological outcomes in pregnant women quarantined at home. Interventions aimed at increasing coping strategies may be more effective for primiparous women during future public health emergencies.

BACKGROUND:Both genetic and environmental factors can influence idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) development. The gut microbiota plays crucial roles in maintaining tissue homeostasis. Dysregulation of the gut microbiota can result in disease. However, whether the alteration of the gut microbiota influences IPF and COPD remains unknown. RESEARCH QUESTION:What is the causal relationship between IPF, COPD and the gut microbiota-related metabolic pathways? What are the potential intermediate mediators in this relationship? STUDY DESIGN AND METHODS:Intersect the gut microbiota and its metabolic pathways associated with IPF and COPD. Utilizing summary data from GWAS in public databases, a two-sample Mendelian randomization (MR) analysis was conducted on the gut microbiota-related metabolic pathway, the aspartate superpathway, in relation to IPF and COPD. Furthermore, we employed a two-step MR to quantify the proportion of influence mediated by monocytes and cDCs on the aspartate superpathway in relation to IPF and COPD. RESULTS:The MR analysis found that the aspartate superpathway decreased the risk of developing IPF and COPD. Monocytes and cDCs acted as intermediary substances, participating in this with influence proportions of 7.88% and 6.27%, respectively. INTERPRETATION:There is a causal link between the gut microbiota-related metabolic pathway, the aspartate superpathway, and IPF and COPD, where the influence is partially mediated by monocytes and cDCs. In clinical practice, we increase the focus on gut microbiota-mediated immune cells in relation to IPF and COPD.

Inflammation exerts an essential role in gestational diabetes mellitus (GDM), but the relationship between peripheral blood inflammatory markers and GDM remains unclear. The purpose of this study was to explore the relationship between inflammatory markers and GDM in US adults. Data were extracted from the National Health and Nutrition Examination Survey. Five inflammatory markers were derived from complete blood count. Survey-weighted multivariable logistic regression models were used to assess the association between inflammatory markers and GDM. Restricted cubic splines and subgroup analyses were conducted to validate the stability of the results. Finally, a total of 2363 women aged 20-44 were included based on specific criteria, with 229 self-reported GDM cases (9.69%). The increased lymphocyte-monocyte ratio (LMR) was associated with the higher risk of GDM, aOR = 1.82 (CI:1.30-2.56). Compared with the lowest tertile, the highest tertile group of LMR showed a significantly increased risk of GDM, aOR = 2.24 (CI: 1.28-2.85). Conversely, the highest tertile group of systemic inflammation response index (SIRI) was negatively associated with GDM, aOR = 0.61 (95% CI: 0.40-0.94). And high platelet-lymphocyte ratio (PLR) levels are related to a lower risk of GDM. No non-linear relationships were observed. Furthermore, subgroup analysis revealed that the association between LMR, SIRI, and GDM remained consistent with the overall results. Our study indicated that LMR, PLR, and SIRI may be potential predictors of GDM. Further large-scale prospective study is needed to investigate the role of LMR, PLR and SIRI in GDM.

Tertiary lymphoid structures (TLSs) have emerged as critical prognostic and immunotherapeutic indicators in cancer, with their clinical significance modulated by spatial distribution patterns and density. Here, we performed integrated single-cell and spatial transcriptomic profiling of 30 gastric cancer (GC) specimens stratified by TLS spatial localization patterns. Comparative analysis shows pronounced enrichment of CXCL13+ T lymphocytes (TLCs), CXCR5+ germinal center B lymphocytes (gc_B cells), LAMP3+CD80+ activated dendritic cells (DCs), and SELP+ACKR1+ high endothelial venule (HEV) cells within intratumoral-TLS (iTLS) rich tumors compared to peritumoral-TLS (pTLS) and desert-TLS (dTLS) tumor subtypes. Multimodal cell-cell interaction analysis and functional experiments demonstrate that HEV expressed VCAM1 and ICAM1 recruits and activates CXCL13+ TLC through the CXCL13-ACKR1 pathway, which promotes TLS formation via CXCL13-CXCR5-dependent crosstalk with B lymphocytes. We further develop a single-cell/spatial TLS signature that captures the cellular ecosystem of iTLS-containing tumor, demonstrating predictive value for immunotherapy outcomes in GC patients.

BACKGROUND:Mounting evidence indicates that nuclear receptors play a critical regulatory role in platelet pathophysiology and thrombotic disorders. Although NR4A (the nuclear receptor subfamily 4 group A) plays an important role in cardiovascular pathophysiology, the expression profile and biological function of NR4A member 1 (NR4A1) in platelets have never been reported. METHODS:We evaluated the functions and the underlying mechanisms of NR4A1 in platelet activation and thrombus formation using platelet-specific NR4A1-deficient mice and NR4A1-specific agonists. Using a hyperlipidemic mouse model and platelets from patients with hypercholesterolemia, we explored the influence of hypercholesterolemia on NR4A1 expression and the effects of NR4A1-specific agonists on platelet hyperreactivity induced by hypercholesterolemia. RESULTS:NR4A1 was expressed in both human and mouse platelets. Platelet-specific NR4A1 deletion accelerated FeCl3-induced carotid arterial occlusive thrombus formation, enhanced collagen/epinephrine-induced pulmonary thromboembolism, and exacerbated microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. NR4A1-deficient platelets exhibited enhanced agonist-induced aggregation responses, integrin αIIbβ3 activation, dense granule release, α-granule release, platelet spreading, and clot retraction. Consistently, pharmacological activation of NR4A1 by specific agonists decreased platelet activation in both mouse and human platelets. Mechanistically, CAP1 (adenylyl cyclase-associated protein 1) was identified as the direct downstream interacting protein of NR4A1. NR4A1 deletion decreased cAMP levels and phosphorylation of VASP (vasodilator-stimulated phosphoprotein), while NR4A1-specific agonists increased cAMP levels and phosphorylation of VASP in platelets. Importantly, NR4A1 expression in platelets was upregulated in the setting of hypercholesterolemia, which was derived from its upregulation in megakaryocytes in a reactive oxygen species-dependent manner. Platelets from hypercholesterolemic patients and mice exhibited hyperreactivity. However, NR4A1-specific agonists significantly inhibited the activation of hypercholesterolemic platelets to the levels of healthy control platelets. CONCLUSIONS:We provide the first evidence that nuclear receptor NR4A1 negatively regulates platelet activation and thrombus formation. NR4A1 may serve as a novel therapeutic target for managing thrombosis-based cardiovascular diseases, especially with hypercholesterolemia.

Advances in single-cell sequencing have transformed our understanding of immune aging by enabling high-resolution dissection of age-associated changes in cellular composition and function. Recent years have seen a surge in studies leveraging single-cell multi-omics to chart immune trajectories across the human lifespan, uncovering previously unrecognized heterogeneity and functional shifts in peripheral immune cells. While these technologies offer unprecedented insights, they also pose significant technical and analytical challenges, including data integration across platforms and populations. In this review, we critically examine landmark studies, compare emerging immune aging clocks, and highlight opportunities for clinical translation. By decoding immune aging at single-cell resolution, we move closer to early detection of immunosenescence, personalized immunomodulation, and precision strategies to extend healthspan in aging populations.

A comprehensive understanding of the evolution of the immune landscape in humans across the entire lifespan at single-cell transcriptional and protein levels, during development, maturation and senescence is currently lacking. We recruited a total of 220 healthy volunteers from the Shanghai Pudong Cohort (NCT05206643), spanning 13 age groups from 0 to over 90 years, and profiled their peripheral immune cells through single-cell RNA-sequencing coupled with single T cell and B cell receptor sequencing, high-throughput mass cytometry, bulk RNA-sequencing and flow cytometry validation experiments. We revealed that T cells were the most strongly affected by age and experienced the most intensive rewiring in cell–cell interactions during specific age. Different T cell subsets displayed different aging patterns in both transcriptomes and immune repertoires; examples included GNLY+CD8+ effector memory T cells, which exhibited the highest clonal expansion among all T cell subsets and displayed distinct functional signatures in children and the elderly; and CD8+ MAIT cells, which reached their peaks of relative abundance, clonal diversity and antibacterial capability in adolescents and then gradually tapered off. Interestingly, we identified and experimentally verified a previously unrecognized ‘cytotoxic’ B cell subset that was enriched in children. Finally, an immune age prediction model was developed based on lifecycle-wide single-cell data that can evaluate the immune status of healthy individuals and identify those with disturbed immune functions. Our work provides both valuable insights and resources for further understanding the aging of the immune system across the whole human lifespan. In this Resource, authors profile peripheral immune cells from a total of 220 healthy volunteers from birth to over 90 years. This revealed that T cells were most affected by aging with divergent aging patterns in different subsets and identified a population of cytotoxic B cells that were enriched in children.

To understand the dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune, and clinical markers of microbiomes from four body sites in 86 participants over 6 years. We found that microbiome stability and individuality are body-site specific and heavily influenced by the host. The stool and oral microbiome are more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. We identify individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlate across body sites, suggesting systemic dynamics influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals show altered microbial stability and associations among microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease.