JCI Insight

The renin-angiotensin system is a well-characterized regulator of tissue homeostasis whose clinical relevance has expanded to include lung disorders such as chronic obstructive pulmonary disease (COPD)-associated emphysema, idiopathic pulmonary fibrosis, and COVID-19. Despite this interest, the cell-specific localization of angiotensin receptors in the human lung has remained poorly defined, in part due to limitations of available antibody reagents. Here, we define the expression patterns of the two predominant angiotensin receptors, AGTR1 and AGTR2, using complementary bulk and single-nucleus transcriptomic datasets from human lung tissue. We demonstrate that these receptors exhibit mutually exclusive, compartment-specific localization, with AGTR1 expressed in lung pericytes and AGTR2 expressed in alveolar epithelial type 2 cells. AGTR1 is detectable in isolated lung pericytes, and spatial colocalization with pericyte markers confirmed within the airspace microvasculature compartment by RNAscope. Airspace pericyte abundance was reduced in an experimental emphysema model but restored by pharmacologic attenuation of AGTR1 signaling commensurate with airspace repair. In COPD lungs, AGTR1 expression showed heterogeneous, disease-associated dysregulation across stromal populations, including upregulation in alveolar fibroblasts. Bulk transcriptomics also revealed aging-associated redistribution of AGTR1 expression into stromal compartments. Angiotensin II and cigarette smoke impaired pericyte migration toward endothelial cells, while combined exposure suppressed pericyte proliferation. Together, these findings identify AGTR1 as a new highly selective marker of lung pericytes and a regulator of pericyte behaviors within the airspace microvasculature. These findings provide a cell-resolved framework for angiotensin signaling with direct relevance to airspace resilience and therapeutic targeting.

Glioblastoma Multiforme (GBM) is a highly aggressive brain cancer characterized by rapid proliferation and extensive remodeling of the extracellular matrix (ECM), leading to progressive tissue stiffening. Although ECM stiffness is known to promote GBM progression, the molecular mechanisms linking mechanical cues to tumor growth remain insufficiently defined. In this study, transcriptomic comparison of GBM tumors and non-neoplastic brain tissue revealed coordinated upregulation of cell cycle regulators and matrisome-associated genes, with survivin (BIRC5) identified as a central node linking proliferative signaling and ECM remodeling networks. Analysis of GBM patient specimens further showed strong nuclear survivin expression in regions with elevated collagen deposition. To directly evaluate stiffness-dependent regulation of survivin, GBM cells were cultured on fibronectin-infused hydrogels with tunable stiffness. Stiff matrices increased survivin expression along with cyclin D1 and cyclin A, consistent with increased cell cycle progression. Pharmacologic inhibition or siRNA-mediated suppression of survivin reduced stiffness-induced proliferation and attenuated expression of matrisome components, including collagens and lysyl oxidase. These findings indicate that survivin functions as a mechanosensitive regulator that coordinates cell cycle progression with ECM production in stiff tumor microenvironments. Collectively, this study identifies survivin as a key mediator linking ECM stiffness to GBM growth and matrisome remodeling. Targeting survivin and its effectors may offer a mechanosensitive strategy to limit GBM growth.

Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive, and fatal interstitial lung disease for which effective therapies remain limited. Alveolar type 2 (AT2) epithelial cells serve as facultative stem cells essential for alveolar repair; however, AT2 cell senescence disrupts epithelial regeneration and contributes to fibrotic remodeling in IPF. Syndecan-1 is a transmembrane heparan sulfate proteoglycan predominantly expressed by lung epithelial cells, but its role in AT2 dysfunction during fibrosis is poorly defined. Here, we demonstrate that syndecan-1 is robustly upregulated in AT2 cells in IPF and other fibrotic lung diseases, as well as in murine bleomycin-induced lung fibrosis. Syndecan-1 expression was further enhanced with aging and associated with increased fibrotic burden in aged mice. Using integrated human transcriptomic analyses, mouse genetic models, and epithelial cell-based systems, we show that excess syndecan-1 promotes cell-autonomous epithelial senescence and impairs AT2 progenitor function. Elevated syndecan-1 reduced AT2 renewal capacity, disrupted differentiation, and diminished surfactant protein C level, whereas genetic loss of syndecan-1 attenuated senescence and preserved epithelial function following injury. Together, these findings identify syndecan-1 as a critical epithelial regulator of AT2 senescence and maladaptive repair in pulmonary fibrosis and support targeting syndecan-1-driven epithelial dysfunction as a potential therapeutic strategy.

Chronic diabetic wounds represent a major clinical burden and are strongly associated with peripheral neuropathy, yet the contribution of nerve-associated Schwann cells to impaired healing remains poorly defined. Here, we investigated Schwann cell dynamics in cutaneous wound repair using the db/db model of type 2 diabetes. Full-thickness excisional wounds in db/db mice exhibited delayed closure, reduced dermal and epidermal thickness, and diminished cellular proliferation compared to non-diabetic controls. Diabetic wounds also demonstrated impaired re-innervation and a marked reduction in both total (S100{beta}+) and dedifferentiated (p75NTR+) Schwann cells, including decreased Schwann cell proliferation. These findings indicate that diabetes disrupts the injury-induced Schwann cell response that is essential for normal repair. Transcriptomic analyses revealed that injury-activated Schwann cells upregulate multiple trophic factors, including oncostatin M (OSM), while single-cell RNA sequencing demonstrated broad expression of OSM receptors (Osmr and Il6st) across wound-resident keratinocytes, fibroblasts, and vascular-associated cells, suggesting widespread responsiveness to OSM signalling during repair. Therapeutic administration of OSM to diabetic wounds significantly accelerated closure, reduced wound width and area, and increased dermal and epidermal thickness. Mechanistically, OSM enhanced epidermal proliferation, angiogenesis, and cutaneous axon regeneration. Collectively, these data identify Schwann cell dysfunction as a contributor to impaired diabetic wound healing and demonstrate that augmenting a Schwann cell-derived paracrine signal can partially rescue key reparative processes. Our findings support a regulatory role for Schwann cells in coordinating epithelial, vascular, and neural repair responses and highlight OSM signalling as a potential therapeutic strategy for chronic diabetic wounds.

Duchenne muscular dystrophy (DMD) is a multisystem disorder affecting striated muscle, metabolism, and the central nervous system (CNS). Although glucocorticoids remain the standard therapy, muscle-centric evaluations typically fail to capture how dosing regimen and compound selection affect CNS and metabolic phenotypes. Here, we compared daily and weekly dosing of prednisolone and vamorolone in juvenile mdx mice over six weeks to determine how these variables influence multisystem outcomes. Multiorgan efficacy and adverse effects were quantified across behavioural, endocrine, metabolic, cardiovascular, and muscle domains using behavioural assays, in vivo and functional muscle testing, haemodynamic evaluation and histopathology. Daily glucocorticoid dosing failed to improve muscle function or strength, whereas weekly vamorolone produced the most robust improvements in functional and in vivo muscle strength. Daily prednisolone reduced circulating creatine kinase levels, but this biochemical change did not translate into enhanced muscle function outcomes. Daily regimens also induced severe adrenal cortical atrophy, yet these endocrine alterations were dissociated from CNS stress and anxiety responses, which remained unchanged by treatment. In addition, daily dosing caused pronounced systemic metabolic consequences, whereas weekly regimens substantially attenuated these effects, identifying dosing frequency as a key determinant of safety. Together, these findings demonstrate that glucocorticoid regimen selection fundamentally reshapes the efficacy-adverse effect profile and underscores the value of integrated multiorgan evaluation in DMD. This work highlights the need to expand therapeutic assessments beyond muscle pathology and raises new questions about how glucocorticoid signalling differentially engages peripheral and central physiological systems.

Lupus nephritis (LN) is a leading cause of morbidity in pediatric systemic lupus erythematosus (pSLE) due to suboptimal kidney remission rates and the sequelae of prolonged intensive immunosuppressive therapy. LN is patchy, with some glomeruli severely damaged while others remain histologically unaffected in the same kidney. Using spatial transcriptomic technology, we interrogated microanatomic transcriptional differences between histologically damaged and unaffected glomeruli in pSLE LN to understand local drivers of renal injury. Despite SLE being a disease of Type I interferon (IFN), IFN gene response does not associate with local glomerular damage. Rather, damage associates with a transcriptional module of higher expression of myeloid cell markers, C5AR1 (encoding the receptor for complement component 5a [C5a]), early complement components, and fibrosis genes. Bulk RNA-sequencing of C5a stimulated human monocyte-derived-macrophages revealed upregulation of tissue-remodeling and fibrosis-related pathways reversible by the C5aR1 inhibiting drug avacopan. These same C5a-inducible fibrosis genes were significantly upregulated in histologically damaged versus unaffected LN glomeruli providing a mechanistic link between C5a-C5aR1 signaling and early fibrosis in proliferative lupus nephritis. Our data provide insight into an understudied connection between complement activation and fibrosis relevant in SLE and likely other inflammatory diseases of complement activation.

Anti-phospholipid (APL) autoantibodies confer a high risk for adverse pregnancy outcomes, especially in Systemic Lupus Erythematosus (SLE). While human TLR8 (huTLR8) has been implicated in APL antibody-mediated placental injury in vitro, its in vivo role in pregnancy is unexplored. We report a novel mouse model of pregnancy loss in SLE-prone mice expressing huTLR8. Placental analysis revealed early developmental defects starting post-implantation, including a thin junctional zone, impaired vascularization, infarcts, and inflammation. Profound immune dysregulation was evident at E8.5 including increased myeloid cells and CD8 T cells and decreased uterine natural killer (uNK) cells. RNA sequencing revealed downregulated pregnancy-specific glycoproteins, reduced uNK cell-associated genes, and an upregulated myeloid cell signature. Bone marrow chimera studies demonstrated preferential activation of huTLR8-expressing placental Ly6C+ monocytes. Spatial transcriptomics at E9.5 confirmed uNK cell loss, decreased IL15 expression by both stromal and myeloid cells, and discrete inflammatory aggregates in the maternal layers containing myeloid cells and IFN{gamma}-expressing CD8 T cells. We propose that huTLR8, likely through myeloid cell activation and cytolytic T cell recruitment, drives placental injury in the context of SLE and APL autoantibodies. This model provides a valuable platform to dissect early pathogenic events in APL-associated pregnancy loss and identify new therapeutic targets.

Key PointsO_LIRenin deficiency in renin-lineage cells worsened crescentic injury and impaired cell migration, revealing a protective role for renin in crescentic glomerulonephritis. C_LIO_LILoss of renin shifted renin-lineage cells signaling toward interferon/STAT1-driven C_LIO_LIRenin-lineage cell ablation in crescentic glomerulonephritis induced a less inflammatory disease time-course. C_LI BackgroundThe adult juxtaglomerular renin-lineage cell (RLC) niche contributes to intraglomerular repair after injury, but their role in highly inflammatory crescentic glomerulonephritis (cGN) remains unclear. While angiotensin II-AT1R signaling promotes fibrosis and inflammation, the contribution of the RLCs, and of renin expression within RLCs, to cGN outcome has not been investigated. MethodsWe used tdTomato lineage-tracing to track RLCs in wild-type (WT) and renin-knockout (RenKO) mice following cGN induction. RLC migration and glomerular injury were quantified histologically. Single-cell RNA sequencing was performed on isolated tdTomato-positive cells at day 10 and 21 after injury to characterize transcriptional programs. Disease progression was additionally examined in mice with diphtheria toxin A-mediated (DTA) RLC ablation. ResultsRLCs were detected within injured glomeruli during cGN, with sporadic localization to crescentic lesions. Genetic renin deletion in RLCs worsened cGN outcomes, with RenKO mice developing increased albuminuria (by 306%), crescent formation (by 50%) and podocyte loss (by 15%) by day 21 compared to WT controls. Renin-deficient RLCs exhibited a reduced intraglomerular migratory response with decreased colocalization with mesangial and podocytes cell markers. Single-cell transcriptomic analysis supports an immunomodulatory reparative phenotype in WT RLCs. In contrast, RenKO RLCs displayed enrichment of interferon-stimulated genes and pathways suppressing cell migration. RLC ablation reduced macrophage infiltration, but did not alter disease progression, suggesting compensatory cellular mechanisms. ConclusionsRenin expression supports the plasticity and injury-associated responses of RLCs during cGN. Loss of renin shifts RLCs toward an interferon-driven inflammatory and antimigratory phenotype that aggravates glomerular injury, while ablation of the RLCs may be compensated without major outcome changes.

Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein and clinically manifests as profound weakness due to motor neuron degeneration. While recent evidence suggests it is a multisystem disorder, the pathological programs in neural and peripheral tissues are poorly understood. We applied spatial transcriptomics to cross-sections from the entire lumbar region of pre-symptomatic SMA and control mice to define early, tissue-wide transcriptional consequences of SMN deficiency. This approach enabled spatially preserved analysis of spinal cord, dorsal root ganglia, muscle, bone, cartilage, bone marrow, adipose, and connective tissues within their native anatomical context. Within the SMA spinal cord, motor neuron associated regions and ventral interneurons exhibited upregulation of neurofilaments, tubulin isoforms, and microtubule transport machinery. Neurofilament changes were largely restricted to motor neurons, and tubulin dysregulation extended broadly across ventral regions. Multiple tissues displayed collagen and extracellular matrix gene dysregulation at post-natal day 4. Skeletal muscle demonstrated fiber type-specific stress responses, including induction of atrophy-associated genes, while bone displayed an osteoclast-dominant transcriptional signature, consistent with accelerated resorption and a pro-osteoporotic state. Bone marrow transcriptomes indicated activation of neutrophil degranulation, innate immune signaling, and osteoclastogenic pathways, identifying bone marrow as an active inflammatory and skeletal regulatory niche in SMA. Adipose tissue exhibited extracellular matrix dysregulation, complement activation, profibrotic TGF-{beta} signaling, and stress-induced lipolysis. These findings reveal that SMN deficiency drives early transcriptional reprogramming across multiple tissues well before motor neuron loss and identify non-neuronal pathological programs that offer therapeutic targets for improving long-term outcomes in SMA.

Pulmonary fibrosis (PF) involves excessive collagen accumulation, yet mechanisms shifting the balance of synthesis and degradation toward net deposition remain unclear. Myeloperoxidase (MPO) inversely correlates with survival in PF. Using the bleomycin model, we found MPO knockout (MPOko) mice were protected from fibrosis, and pharmacological MPO inhibition after peak inflammation (day 7) recapitulated this protection. MPO persisted in lung tissue 21 days post-injury despite neutrophil efflux, linking acute inflammation to sustained remodeling. Mechanistically, we identified that MPO inhibits Cathepsin K (CatK), a potent collagenolytic enzyme involved in fibrosis resolution. Notably, CatK gene expression (CTSK) is elevated in PF, suggesting post-translational inhibition of CatK. MPOko and inhibitor-treated mice exhibited elevated CatK activity after bleomycin; exogenous addition of pathophysiologic concentrations of MPO reduced CatK activity in mouse precision-cut lung slices and human fibroblasts. Biochemically, MPO reduced CatK activity to 33% of control. In two distinct cohorts of PF patients, we observed significantly increased MPO protein levels in platelet poor plasma and in lung tissue. In PF patients, 62% had MPO levels in platelet poor plasma exceeding healthy controls, while lung tissue from other PF patients showed significantly elevated MPO staining. Plasma levels were inversely correlated with decreased survival, FVC, and DLCO. These findings establish MPO as a post-translational inhibitor of CatK-mediated collagenolysis, revealing a mechanism linking acute inflammation to sustained fibrosis and suggest a patient subpopulation that may benefit from MPO-targeted therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=54 SRC="FIGDIR/small/713467v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@d8fc5eorg.highwire.dtl.DTLVardef@1a088fcorg.highwire.dtl.DTLVardef@818b7dorg.highwire.dtl.DTLVardef@ecdca0_HPS_FORMAT_FIGEXP M_FIG C_FIG Myeloperoxidase persists in lung tissue after injury and inhibits cathepsin K activity, impairing collagen degradation and promoting extracellular matrix accumulation during pulmonary fibrosis.

ObjectiveAutoimmune diseases (ADs) markedly elevate venous thromboembolism (VTE) risk, yet the shared genetic architecture and tissue-specific regulatory mechanisms of this "Autoimmune-Thrombotic Axis" remain poorly defined. We aimed to characterize the genomic landscape of immunothrombosis to identify causal links and therapeutic targets. Approach and ResultsWe integrated large-scale GWAS data for VTE and 16 ADs using a multi-omics framework, including pleiotropy scanning, local genetic correlation, and summary-based Mendelian randomization (SMR). We identified 21 Immunothrombotic Shared Loci (ISLs) and 274 pleiotropic genes enriched in complement and coagulation cascades. Mendelian randomization (MR) analysis revealed a robust causal effect of genetically predicted systemic lupus erythematosus (SLE) on VTE risk (OR = 1.018, 95% CI: 1.008-1.029, P = 0.0003). Mechanistically, IL6R and PLCL1 emerged as central mediators with distinct tissue-specific regulatory partitioning. Colocalization confirmed that shared genetic susceptibility is primarily driven by expression in arterial tissues (aorta and coronary) rather than exclusively in immune cells. Furthermore, the lead SNP rs4129267 was identified as a potential predictor for VTE in rheumatoid arthritis patients, and drug prioritization nominated TNF inhibitors as promising candidates for mitigating thrombotic burden. ConclusionThis study establishes the first genomic atlas of the autoimmune-thrombotic axis, demonstrating that vasculature-specific gene regulation drives immunothrombosis. These findings provide a biological basis for VTE risk stratification and suggest that genotype-guided therapy may optimize vascular outcomes in AD patients.

Acute antibody-mediated rejection (aABMR) is an important cause of clinical kidney graft injury and failure. Transcripts associated with NK cell activation in graft biopsies are diagnostic of aABMR, but mechanisms underlying NK cell activation during ABMR remain poorly understood. In contrast to the long-term (> 60 days) survival of complete MHC-mismatched kidney allografts in wild type C57BL/6 mice, B6.CCR5-/- recipients develop high titers of donor-specific antibody (DSA) with allograft rejection between days 18 to 28 post-transplant. This has allowed investigation of mechanisms underlying NK cell activation within kidney allografts during aABMR. DSA titers first became detectable in B6.CCR5-/- (H-2b) recipients of A/J (H-2a) kidney allografts at day 8 and peaked on day 15 post-transplant and was accompanied by a parallel increase in mRNA levels of Rae-1e, a ligand for the NK cell activation receptor NKG2D. A/J kidneys in B6.CCR5-/-NKG2D-/- recipients and A/J.Rae-1e-/- kidneys in B6.CCR5-/- recipients survived >60 days, despite high serum DSA levels. Flow cytometric analysis of allograft infiltrating cells in B6.CCR5-/- recipients on day 15 post-transplant revealed inflammatory monocyte and NK cell infiltration and NK cell activation to proliferate and express CD107a, a marker of cytotoxic function. These features of aABMR were absent or markedly reduced by recipient NKG2D- or donor graft Rae-1e-deficiency. These findings suggest that interference with expression of allograft Rae-1e or recipient NK cell NKG2D abrogates aABMR despite persistently high DSA levels and that aABMR requires coordination between infiltrating NK cell and inflammatory monocyte activation within the kidney allograft.

Idiopathic Pulmonary Fibrosis (IPF) is an incurable disease with extensive molecular, cellular, and organ level dysfunction. A major gap in IPF research is the lack of understanding of how short-term cellular behavior causes long-term tissue remodeling. By optimizing lung slices from explanted human lungs, we discovered foci of migratory non-canonical alveolar type 2 (AT2) cells in regions of established lung fibrosis and found that these cells are trapped in states of cellular transition that are driven by persistent developmental repair programs. Consistent with these biophysical behaviors, pharmacological activation of {beta}-catenin reproduced persistent migration, whereas YAP activation restrained it. We conclude that imbalanced developmental programs drive AT2 cell motility and lesion heterogeneity, providing a mechanistic link between short-term cellular dynamics and slowly progressive fibrosis of IPF.

Peripheral pain sensation is regulated by interactions between sensory nerves and various tissue cells. In obese patients with painful small fiber neuropathy, skin sensory nerves are often hypersensitive. While obesity is known to cause circulation-related vascular abnormalities, how these changes affect sensory dysfunction is not fully understood. In this study, we found that in a diet-induced obesity mouse model, skin capillaries become fenestrated, allowing insulin to diffuse into the avascular epidermis. This exposure triggers the production and secretion of nerve growth factor (NGF) from epidermal keratinocytes via insulin signaling with the forkhead box O1 (FOXO1) transcription factor. Elevated NGF leads to heightened sensory hypersensitivity by enhancing transient receptor potential vanilloid subtype 1 (TRPV1) in sensory nerves. Controlling capillary permeability reduces abnormal NGF expression and attenuates pain hypersensitivity. These findings nominate peripheral nerve-associated capillary permeability as a novel therapeutic target in obesity-associated sensory dysfunction.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by immune dysregulation and barrier dysfunction. To define the molecular architecture of AD in greater detail, we integrated lesional (LES) and non-lesional (NLS) transcriptomic data from multiple datasets using gene expression data from normal skin and psoriasis (PSO) and nummular eczema (NME) cohorts as reference. Gene set variation analysis revealed that adult AD exhibits broad immune activation and consistent barrier impairment in both LES and NLS skin, whereas pediatric AD is dominated by IL-1-driven inflammation with minimal barrier alteration. Comparative analyses showed stronger Th2 and myeloid activity in AD, metabolic enrichment in PSO, and complement and NK cell activation in NME. Longitudinal profiling identified temporal variation in Th1, Th2 and IFN pathways in AD skin. An eczema immune and cellular score, ECZECIS, was developed to quantify transcriptomic abnormalities and correlated with clinical improvement following dupilumab therapy. Among all treatments analyzed, dupilumab produced the most extensive reduction of immune and cytokine pathway activity in skin and attenuated systemic immune activation in blood. These findings delineate distinct immune and barrier signatures across age groups and disease types and establish ECZECIS as a quantitative biomarker for monitoring molecular treatment response in AD.

Semaglutide has shown benefit in metabolic dysfunction-associated steatohepatitis (MASH), but real-world evidence across longitudinal liver phenotypes remains limited, particularly regarding how liver remodeling relates to weight loss and dose exposure. Using a de-identified federated electronic health record network spanning more than 29 million patients in the United States, including 489,785 semaglutide-treated adults, we analyzed 6,734 patients with baseline liver disease burden. We find that higher attained pre-landmark (0-2 years) semaglutide dose was associated with lower post-landmark (2-4 years) risk of steatohepatitis, alcoholic liver disease, and all-cause mortality, whereas greater pre-landmark weight loss was associated with lower post-landmark risk of steatohepatitis, steatotic liver disease, and hepatorenal syndrome, indicating distinct dose- and weight-linked patterns of long-term liver benefits. These associations were notable because semaglutide prescribing was generally lower during the post-landmark period, raising the possibility of durable benefit beyond peak exposure. Towards better understanding mechanistic bases for liver protection, we performed a complementary longitudinal study of 326 adults with paired noninvasive liver elastography measurements before and after treatment initiation. Median liver stiffness decreased from 4.85 [3.02 - 7.20] to 3.9 [2.6 - 5.8] kPa after semaglutide initiation (median change = -0.38 kPa; p<0.001), with 194 of 326 patients (59.5%) showing lower follow-up stiffness. A clinically meaningful reduction of at least 20% was observed in 133 of 326 patients (40.8%), and 69 of 326 (21.2%) shifted to a lower fibrosis stage by prespecified elastography thresholds. Larger improvements were also seen in patients with higher baseline stiffness (p<0.001); notably 80% of patients with cirrhosis-range baseline stiffness ([&ge;]12.5 kPa) achieved [&ge;]20% improvement versus 29.5% with minimal baseline disease (p <0.001). The proportion achieving at least 20% stiffness improvement was similar across weight-loss strata, including patients with no weight loss or weight gain and those with at least 10% weight loss (38.0% in each group), and liver stiffness change showed negligible correlation with changes in weight, BMI, HBA1c, alanine aminotransferase, or aspartate aminotransferase. To provide biological context, single cell RNA analyses demonstrated sparse overall hepatic GLP1R expression (0.0239%), with enrichment in non-parenchymal niches including cholangiocytes, intrahepatic cholangiocytes, liver sinusoidal endothelial cells, and hepatic stellate cells implicated in fibrogenesis and vascular remodeling. Together, this real-world evidence suggests diverse liver benefits for semaglutide beyond weight-loss with intricate dose response relationships.

BackgroundPrimary mitral regurgitation resulting from mitral valve prolapse can lead to life-threatening complications, including arrhythmias, heart failure, and sudden cardiac death. Mitral valve prolapse is classically associated with myxomatous mitral valve degeneration, characterized by leaflet thickening, extracellular matrix disorganization, and progressive structural remodeling. Valvular interstitial cells, the predominant stromal population within the valve, maintain extracellular matrix homeostasis; however, their molecular heterogeneity, and state-specific contributions to disease pathogenesis remain incompletely defined. MethodsUsing a fibrillin-1 deficient mouse model and human tissue specimens we integrated single-cell RNA sequencing with spatial transcriptomic profiling to construct a comprehensive atlas of cellular composition and extracellular matrix organization across normal mitral valves, sporadic mitral valve prolapse, and Marfan syndrome-associated mitral valve prolapse. ResultsAnalyses revealed spatially organized cellular niches and substantial heterogeneity within the valvular interstitial cell population. Across murine and human datasets, we identified a conserved activated valvular interstitial cell population enriched for profibrotic extracellular matrix remodeling programs and preferentially localized to mechanically vulnerable leaflet tip regions. This population exhibited coordinated upregulation of collagen- and matrix-associated genes, metabolic signatures consistent with enhanced mitochondrial activity, and transcriptional features suggesting fibro-inflammatory signaling. ConclusionsWe identified a transcriptionally and spatially distinct activated valvular interstitial cell state conserved across species and disease etiologies that is strongly implicated in fibrotic remodeling during myxomatous mitral valve degeneration and provides a candidate therapeutic target.

Prioritising malaria vaccine targets requires understanding immunity to genetically and structurally diverse parasite antigens, influencing antibody measurements and durability. We measured total IgG levels to 25 Plasmodium falciparum antigens and assessed their association with protection and antigen features. Antibodies were quantified in two longitudinal cohorts of Papua New Guinean children (5-14 years; n=647) experiencing high or moderate transmission. Associations between antibody levels and time to first clinical malaria episode were evaluated using Cox regression and Bayesian antibody-kinetics models, incorporating antigen genetic diversity and structural properties. In high-transmission settings, antibody levels were elevated and stable, with the strongest protection observed for conserved, low-diversity antigens dominated by the 3D7 variant and enriched for intrinsically disordered and alpha-helical regions. In moderate transmission, antibody levels were variable, decayed over time, and reflected recent exposure. These findings identify antigen diversity as a key modifier of malaria immunity and underscore the importance of antigen features.

RationaleProgressive fibrosing interstitial lung disease features "advancing fronts" where new matrix is deposited, but the signals sustaining these propagating niches remain incompletely defined. ObjectivesTo determine the spatial and temporal compartments in which HIF-1 operates during fibrotic progression and to test whether myeloid HIF-1 is a tractable driver of lesion propagation. MethodsWe integrated human IPF datasets, clinical severity profiling, sarcoidosis peripheral blood immune phenotyping, multiplex immunofluorescence and spatial mapping in human lung tissue, single-cell transcriptomic analyses, and temporally staged bleomycin lung injury with genetic and lung-directed therapeutic perturbations. Measurements and Main ResultsIn the Lung Genome Research Consortium cohort, HIF1A expression was increased in IPF lungs and correlated with higher GAP scores. In sarcoidosis, circulating monocytes from patients with progressive disease exhibited increased HIF-1 compared with those with resolving disease. In IPF lungs, nuclear HIF-1 localized predominantly to CD68 macrophages and PDGFR fibroblasts concentrated within collagen-rich, SMA advancing fronts, and single-cell analyses demonstrated enrichment of HIF-1-linked transcriptional programs consistent with macrophage-fibroblast crosstalk (including pro-fibrotic growth factors, chemokines, and matrix-regulatory pathways). In bleomycin-induced fibrosis, HIF-1 activity emerged first in macrophages and subsequently in fibroblasts within pimonidazole-marked hypoxic rims bordering nascent SMA foci. Myeloid-specific Hif1a deletion reduced front-associated macrophage persistence, attenuated fibroblast activation, and decreased collagen deposition. Two lung-directed strategies, inhaled liposomal echinomycin and inhaled shHif1a lipid nanoparticles, phenocopied these effects, demonstrating therapeutic tractability. ConclusionsThese findings define a hypoxic front-zone niche in which myeloid HIF-1 sustains macrophage persistence and promotes fibroblast activation and matrix remodeling. By linking spatial compartmentalization to causal genetics and lung-directed intervention, our work identifies myeloid HIF-1 as a mechanism-anchored, locally targetable driver of fibrotic lesion propagation.

Asthma is the most common chronic respiratory disease of childhood and is strongly associated with genetic variants at the 17q21 locus that increase expression of ORMDL3, a negative regulator of serine palmitoyl-CoA transferase (SPT), the rate-limiting enzyme in de novo sphingolipid synthesis. Reduced sphingolipid production has been linked to airway hyperreactivity, a key physiological feature of asthma, but the mechanisms connecting altered sphingolipid metabolism to airway dysfunction remain unclear. We examined whether sphingolipid metabolites regulate airway smooth muscle reactivity. Circulating sphingolipids were quantified in children with asthma carrying 17q21 risk alleles and in mice with reduced SPT activity. Functional airway responses were assessed in precision-cut lung slices exposed to sphingosine-1-phosphate (S1P), sphinganine-1-phosphate (Sa1P), and S1P receptor antagonists. Homozygous carriers of the rs7216389 risk allele and SPT-deficient mice displayed an increased S1P-to-Sa1P ratio. In functional assays, Sa1P opposed S1P-induced airway contraction, and increasing Sa1P availability reduced airway hyperresponsiveness. These findings identify the S1P/Sa1P axis as a metabolic rheostat regulating airway smooth muscle tone and suggest that targeting sphingolipid metabolism may offer a therapeutic strategy to mitigate intrinsic airway hyperreactivity in asthma. One sentence summaryAn imbalance between sphingosine-1-phosphate and sphinganine-1-phosphate links the asthma risk locus 17q21 to airway hyperreactivity and reveals sphingolipid metabolism as a potential therapeutic target.