GSK4024484 / GSK - LARVOL DELTA

A Study to Investigate the Safety of GSK4024484 in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=156 | Recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Aug 2025 ➔ Aug 2026 | Trial primary completion date: Aug 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date • Infectious Disease • Malaria

Targeting the Toll-Like Receptor 4 Ameliorates Heart Failure in Aged Mice by Inhibiting the Formation of Neutrophil Extracellular Traps. (PubMed, Physiol Res) - "Thereafter, mice received daily intraperitoneal injections of the TLR4 inhibitor TAK-242 (2 mg/kg), deoxyribonuclease I (DNase I, 5 mg/kg), or the peptidylarginine deiminase 4 (PAD4) inhibitor GSK484 (4 mg/kg) for 7 consecutive days. Targeting TLR4 can mitigate inflammatory responses and enhance cardiac function in HF mice by inhibiting NETs formation. Key words Heart failure " Cardiac function " Inflammation " Toll-like receptor 4 " Neutrophil extracellular traps."

IO biomarker • Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • ELANE • IL1B • IL6 • MPO • TLR4 • TNFA

IL-17A Promotes NETs Formation via the PKCζ-ERK-ROS-PAD4 Pathway in a Mouse Model of Ischemic Stroke. (PubMed, CNS Neurosci Ther) - "IL-17A promotes NETs formation by upregulating PAD4 through the PKCζ-ERK-ROS pathway, exacerbating ischemic brain injury. Targeting this axis may offer a novel therapeutic strategy for stroke."

Journal • Preclinical • Cardiovascular • CNS Disorders • Ischemic stroke • Vascular Neurology • IL17A • MPO

NETosis-Dependent Generation of Immunodeficient Low-Density Neutrophils Exacerbates Sepsis-Induced Acute Lung Injury. (PubMed, Int J Mol Sci) - "In vivo, the NETosis inhibitor GSK484 reduced LDN generation and alleviated sepsis-associated ALI. In conclusion, sepsis induces the generation of immunodeficient LDNs via a NETosis-dependent pathway, which exacerbates lung injury. Targeting this pathway may represent a novel therapeutic strategy for sepsis."

Journal • Acute Lung Injury • Infectious Disease • Respiratory Diseases • Septic Shock

High-throughput chemical proteomics workflow for profiling protein citrullination dynamics. (PubMed, Nat Commun) - "Applying this workflow to primary human neutrophils, we successfully monitor dynamic regulation, quantifying dose-dependent activation and inhibition by the PAD4 inhibitor GSK484...Notably, extensive citrullination of linker histone H1 and structural proteins like lamin B1 suggests broad remodeling of cell architecture during NET formation. This workflow enables proteome-wide mapping of citrullination sites and facilitates its study across diverse biological contexts."

Journal • Immunology • Inflammation • LMNB1

Neutrophil methylmalonic acid promotes microthrombus formation and adverse cardiac remodeling post-myocardial infarction through activating IL-6 signaling pathway-mediated NETosis. (PubMed, BMC Med) - "Neutrophil-derived MMA promotes NETosis and microthrombus formation through IL-6 activation, contributing to maladaptive cardiac remodeling post-MI. These findings identify neutrophil MMA as a novel immunometabolic trigger driving NET-mediated adverse cardiac remodeling and suggest colchicine as a promising therapeutic strategy to prevent heart failure post-MI, particularly in patients with elevated neutrophil MMA contents."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Disorders • Myocardial Infarction • Thrombosis • IL6 • JAK1

PPARγ agonism ameliorates acute kidney injury by inhibiting neutrophil extracellular trap formation-mediated renal tubular epithelial cell PANoptosis. (PubMed, Cell Commun Signal) - "PPARγ is a pivotal checkpoint in CP-AKI by inhibiting ROS-NETosis-driven AIM2-mediated PANoptosis. This protective mechanism is also applicable to IRI-induced AKI, highlighting its broad relevance. HD-1L confers renoprotection through PPARγ activation, providing a novel therapeutic strategy against AKI."

Journal • Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • CASP3 • PPARG

MicroRNA-223/NE Signaling Pathway Inhibits Lipopolysaccharide-Induced Acute Lung Injury by Regulating Neutrophil Extracellular Traps. (PubMed, Mediators Inflamm) - "The roles of the miR-223/NE/NETs axis were further investigated using the NETs inhibitor GSK484 and the NE inhibitor Sivelestat. This study reveals that the miR-223/NE axis critically regulates NETs formation, modulating neutrophil inflammatory infiltration and neutrophil-epithelial interactions to exacerbate ALI. These findings provide potential therapeutic targets for ALI."

Journal • Acute Lung Injury • Inflammation • Respiratory Diseases • ELANE • IL1B • IL6 • MIR223 • MPO • TNFA

NLRP3 Inflammasome Activation Modulates Neutrophil Extracellular Trap Formation and Aggravates Airway Inflammation in Bronchiectasis. (PubMed, Research (Wash D C)) - "Both MCC950 and Z-VAD-FMK inhibited NLRP3 inflammasome activation, whereas GSK484 and LDC7559 suppressed NET formation. Collectively, NLRP3 inflammasome activation facilitates NET formation in bronchiectasis, aggravating inflammation and eliciting injury to epithelial cells."

Journal • Bronchiectasis • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • ELANE • IL1B • MPO • MUC5AC • NLRC5 • NLRP3 • TJP1

NRAS mutation drives excessive netosis and differentiation syndrome in acute promyelocytic leukemia (ASH 2025) - "Background Acute promyelocytic leukemia (APL) is highly curable with all-trans retinoic acid (ATRA) and arsenictrioxide (ATO)...Inhibitors targeting CXCR1/2 (Reparixin), NE(Sivelestat), MEK(Trametinib), PAD4(GSK484), and JAK1/2 (Ruxolitinib) were applied to evaluate their inhibitory effects onNETosis and differentiation...Targeting this pathway with reparixin or sivelestatattenuates NET formation without compromising cell differentiation, offering a promising therapeuticstrategy to mitigate DS-induced tissue damage while preserving anti-leukemic efficacy. These findingsprovide mechanistic insights into NRAS-driven inflammation in APL and support NETs-targeted therapyfor prophylaxis of DS."

Acute Promyelocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Thrombosis • ANXA5 • CXCL8 • CXCR1 • ICAM1 • ITGAM • JAK1 • JAK2 • NRAS • VCAM1

Hepatocyte-derived extracellular vesicles carrying damaged mitochondria drive neutrophil extracellular traps formation and exacerbate acetaminophen-induced liver injury. (PubMed, Int Immunopharmacol) - "APAP-injured hepatocytes release EVs enriched with damaged mitochondrial cargo that activate cGAS-STING-dependent NETs formation, thereby amplifying liver injury. Targeting EVs biogenesis or NETs formation may provide effective therapeutic strategies for APAP-induced hepatotoxicity."

Journal • Hepatology • Liver Failure

NETs in ovarian cancer progression: innovative nanoparticle-based therapeutic strategies. (PubMed, Eur J Med Res) - "To exploit this vulnerability, we propose a multifunctional nanoparticle platform co-delivering GSK484, a selective anti-NETosis agent, alongside a potent cytotoxic drug...Implementation of this approach could refine patient stratification, enhance response rates, reduce recurrence, and translate into tangible survival benefits. This review highlights NETs as central orchestrators of ovarian cancer progression and presents a translationally actionable nanomedicine strategy poised to transform clinical outcomes in a malignancy long plagued by therapeutic failure."

Journal • Review • Immunology • Oncology • Ovarian Cancer • Solid Tumor

Citrullination of fibrin by PAD4 is an important contributor to fibrinolytic deficiency in pleural infection (BTS WM 2025) - "Subsequent ex vivo experiments showed an increase in the level of D-dimers in the presence of the PAD4 inhibitor GSK484, tPA and Dnase ( p = 0.0003), confirming the contribution of citrullinated fibrin to fibrinolytic deficiency...Conclusion Our data suggests that the citrullination of fibrin contributes to fibrinolytic deficiency and hence the formation of fibrous septations. Our data also suggests that PAD4 inhibitor could potentially improve pleural fluid drainage."

Infectious Disease

Cholesterol Crystals and Neutrophil Extracellular Traps: Drivers of Thromboinflammation in Atherosclerosis and Gastrointestinal Cancers. (PubMed, Catheter Cardiovasc Interv) - "DNase I and heparin disrupt NET scaffolds, while PAD4 inhibitors (e.g., GSK484) block NET generation. Colchicine demonstrates dual anti-inflammatory and NETosis-inhibitory effects, and lipid-lowering agents (statins, PCSK9 inhibitors) mitigate CC burden. Nanotherapies, such as HDL-mimetic nanoparticles, offer targeted delivery to restore immune surveillance. This review highlights the need for personalized, biomarker-guided therapies to disrupt the pathogenic CC-NET axis proposing an integrated approach to mitigate CC-mediated damage in cardiovascular and gastrointestinal oncologic disease."

Journal • Review • Atherosclerosis • Cardiovascular • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Oncology • Pancreatic Cancer • Solid Tumor • Thrombosis • IL1B • NLRP3 • TLR4

PAD4 promotes macrophage migration to aggravate tubulointerstitial injury in diabetic kidney disease. (PubMed, Mol Ther) - "Both PAD4 deficiency in macrophages and PAD4 inhibitor GSK484 significantly alleviated renal tubulointerstitial injury by reducing macrophage infiltration in diabetic mice models. Mechanistically, PAD4 interacted with p65 to promote its binding to Cmklr1 promoter and induce the expression of Cmklr1, which led to an enhanced macrophage migration. These findings demonstrate the crucial role of PAD4-mediated macrophage migration in tubulointerstitial injury of DKD."

Journal • Diabetic Nephropathy • Nephrology • Renal Disease

Surgery-Induced Neutrophil Extracellular Traps Promote Tumor Metastasis by Reprogramming Cancer Cell Lipid Metabolism. (PubMed, Cancer Res) - "Perioperative inhibition of NET formation utilizing DNAse, GSK484, or PAD4 knockout mice prevented surgically induced tumor growth, whereas pre-treating cancer cells with NETs in vitro before inoculation increased tumor burden...Blocking FAO with etomoxir, a CPT1α inhibitor, prevented metastatic tumor growth induced by surgical NETs...Analysis of patient data substantiated the correlation between NET abundance and lipid metabolism, and plasma from post-operative patients upregulated CD36 expression and promoted the proliferation of colorectal cancer cells. Together, these findings show that the systemic NETosis response triggered by surgery promotes tumor progression by activating the MYC transcriptional program and reprogramming FAO metabolism in cancer cells."

Journal • Colorectal Cancer • Metabolic Disorders • Oncology • Solid Tumor • CD36 • SCARB1

Peptidylarginine deiminase 4 deficiency alleviates hypoxia/reoxygenation-induced cardiomyocyte injury. (PubMed, PLoS One) - "Our study is the first to demonstrate that PAD4 expression in cardiomyocytes contributes to H/R injury independent of systemic immune responses and NETs. Consequently, PAD4 may serve as a therapeutic target to alleviate I/R injury."

Journal • Cardiovascular • Coronary Artery Disease • Inflammation • Myocardial Infarction • Myocardial Ischemia • Reperfusion Injury • CASP3

Formation of neutrophil extracellular traps in the early stages exacerbate the healing process by regulating macrophage polarization in Achilles tendon-bone injury. (PubMed, J Tissue Eng) - "Mice underwent Achilles tendon-bone injury and divided into four groups: sham operation, tendon injury (TI) treated with acetylcellulose (vehicle control), TI treated with a Protein arginine deiminase-4 (PAD4) inhibitor GSK484, and TI treated with a neutrophil elastase inhibitor Sivelestat. nlsNETs promote early-phase tendon-bone injury by inducing M1 macrophage polarization and peritendinous fibrosis. Targeting NETs during the initial phase of tendon injury could potentially facilitate the healing process."

Journal • Fibrosis • Immunology • Inflammation • ELANE

PAD4 Promotes Macrophage Migration To Aggravate Tubulointerstitial Injury In Diabetic Kidney Disease (ENDO 2025) - "Both PAD4 deficiency in macrophages and PAD4 inhibitor GSK484 significantly alleviated renal tubulointerstitial injury by reducing macrophage infiltration in diabetic mice models. Mechanistically, PAD4 interacted with p65 to promote its binding to Cmklr1 promoter and induce the expression of Cmklr1, which led to an enhanced macrophage migration. These findings demonstrate the crucial role of PAD4-mediated macrophage migration in tubulointerstitial injury of DKD."

Chronic Kidney Disease • Diabetic Nephropathy • Nephrology • Renal Disease

Formononetin From Sophora flavescens Aiton Alleviates Atopic Dermatitis by Suppressing Neutrophil Extracellular Traps. (PubMed, Phytother Res) - "Co-treatment with PAD4 inhibitor GSK484 and molecular docking were used to study the underlying mechanisms. The study identified FMN as an important active component in Kushen, which showed therapeutic effects comparable to dexamethasone in AD models...These findings highlight FMN as a primary anti-AD constituent of Kushen, therapeutically suppressing NETs-driven crosstalk of innate and adaptive immunity. FMN's multitarget mechanisms provide mechanistic insights and position it as a candidate for AD treatment."

Journal • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • MPO

Clinical and Experimental Insights into the Role of NETosis in IgA Nephropathy Pathogenesis. (PubMed, Kidney Dis (Basel)) - "Mice were treated with the peptidyl arginine deiminase-4 inhibitor GSK484 to evaluate the effects of NETosis inhibition...Our findings demonstrate that NETosis is upregulated in IgAN and plays a key role in its pathogenesis by promoting inflammatory cytokine release. Inhibition of NETosis improves both clinical and pathological outcomes, highlighting its potential as a therapeutic approach for managing IgAN."

Journal • Glomerulonephritis • IgA Nephropathy • Immunology • Oncology • Renal Disease • ELANE • MPO • PPARA

PADI4-mediated citrullination of histone H3 stimulates HIV-1 transcription. (PubMed, Nat Commun) - "PADI4 inhibition by the small molecule inhibitor GSK484 reduces HIV-1 transcription after T cell activation in ex vivo cultures of CD4+ T cells from people living with HIV-1 in a cross-sectional study...Inhibiting PADI4 leads to compaction of the HIV-1 promoter chromatin and an increase of heterochromatin protein 1α (HP1α)-covered heterochromatin, in a mechanism partly dependent on the HUSH complex. Our data reveal a novel mechanism to explain HIV-1 latency and transcriptional regulation."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

The citrullinating enzyme PADI4 binds to lipids: Identification of new target interactions for cancer therapy. (PubMed, J Mol Biol) - "The use in cellulo of a specific enzymatic inhibitor of PADI4, GSK484, abolished the binding between PADI4 and PS in cancer cells, further indicating that their interaction occurred at the protein active site. Altogether, this work shows that PADI4 was capable of binding to lipids, and opens the venue to study the role that it could be playing in deimination processes and cancer development. Moreover, this study lays the foundation for developing novel cancer therapies from new perspectives, based on the interaction of lipids with citrullinating enzymes."

Journal • Metabolic Disorders • Oncology

The deficiency of TMPRSS9 exacerbates the formation of venous thromboembolism through the mediation of neutrophil extracellular traps (ISTH 2025) - "Pad4 knockout or treatment with NETosis-targeted drugs (GSK484, DNase1) could alleviate the degree of venous thromboembolism...In the case-control studies of the validation cohort, mutations in the TMPRSS9 gene, rs62120714 and rs735911, were found to have a higher risk of thrombosis, and higher levels of NETosis formation were also observed in individuals carrying these mutations. Table or Figure Upload"

Cardiovascular • CNS Disorders • Hematological Disorders • Inflammation • Vascular Neurology • Venous Thromboembolism

Experimental study of targeting PAD4 to inhibit the formation of neutrophil extracellular trap network for the treatment of gout (EULAR 2025) - "The differential gene expression profiles of peripheral blood neutrophils were initially constructed for both gout patients and asymptomatic hyperuricemia patients. A notable subpopulation, S100A12+ neutrophils, which is relatively abundant in gout patients, was identified. The target gene PADI4 was included among its marker genes."

Gout • Inflammatory Arthritis • Rheumatology • PADI4 • S100A12 • TRAP