GSK4024484 / GSK - LARVOL DELTA

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

Neutrophil Extracellular Traps Promote AIM2-Dependent Microglial Pyroptosis Following Stroke. (PubMed, Aging Dis) - "Pharmacological inhibition of NET formation with GSK484, a selective protein-arginine deiminase type 4 antagonist, suppressed NET production, reduced absent in melanoma 2 (AIM2) inflammasome expression, and improved neurological outcomes in mice following stroke...These findings suggest that neutrophils in peripheral blood infiltrate the brain parenchyma to generate NETs, activating the AIM2 inflammasome in microglia and exacerbating stroke-induced brain injury through pyroptosis. Targeting NET formation or AIM2 inflammasome activation represents a potential therapeutic strategy for attenuating post-stroke neuroinflammation and secondary neuronal damage."

Journal • Cardiovascular • CNS Disorders • Ischemic stroke • Melanoma • Oncology • Solid Tumor • Vascular Neurology • AIM2

The PAD4 inhibitor GSK484 diminishes neutrophil extracellular trap in the colon mucosa but fails to improve inflammatory biomarkers in experimental colitis. (PubMed, Biosci Rep) - "Treatment groups received daily oral administration of MPO inhibitor (AZD3241; 30 mg/kg) and/or intraperitoneal injection of PAD4 inhibitor (GSK484; 4 mg/kg) 4 times over 9 Inhibition of PAD4 significantly diminished NET density in the colonic mucosa of mice insulted with DSS, reaching levels similar to that detected in control mice. The selected dosage of PAD4 inhibition also yielded no effect on inflammatory markers and antioxidant protein levels. These data sets suggest that other mechanisms may be involved in the pathogenesis of IBD, and the appropriate dosage of GSK484 requires thorough investigation."

Biomarker • Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • ELANE • MPO

Inhibition of Neutrophil Extracellular Traps: A Potential Therapeutic Strategy for Hemorrhagic Stroke. (PubMed, J Integr Neurosci) - "Inhibitors of NET formation, such as the PAD4-specific inhibitor GSK484, are effective at preventing inflammation and thus ultimately reducing brain damage after stroke. In conclusion, inhibition of NETs offers a potential therapeutic strategy for hemorrhagic stroke, although further research is needed to clarify the role of NETs in this condition."

Journal • Review • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Inflammation • Vascular Neurology • HMGB1 • MPO

Simvastatin mitigates ventilator-induced lung injury in mice with acute respiratory distress syndrome via a mechanism partly dependent on neutrophil extracellular traps. (PubMed, Eur J Med Res) - "Simvastatin attenuated VILI in mice with ARDS, potentially via reductions in neutrophil extracellular traps (NETs) generation and apoptosis."

Journal • Preclinical • Acute Lung Injury • Acute Respiratory Distress Syndrome • Pulmonary Disease • Respiratory Diseases • ELANE

Neutrophil damage liver regeneration after hepatectomy in MASLD mice through Neutrophil extracellular traps (APASL 2025) - "Neutrophils impaired liver regeneration after hepatectomy in MASLD mice by producing NETs. Inhibition of neutrophils migration by SB225002 and inhibition of NETS production by GSK484 promoted liver regeneration in MASLD mice."

Preclinical • Hepatology • Liver Failure • Metabolic Dysfunction-Associated Steatotic Liver Disease • CXCL1 • CXCR2

The role of neutrophils in venous thrombosis in primary membranous nephropathy. (PubMed, Am J Nephrol) - "This study preliminarily indicated that neutrophils were involved in the hypercoagulation state and increased thrombosis propensity in PMN, offering novel insights into the pathogenesis of thrombosis formation in PMN and potential therapeutic targets for its management."

Journal • Cardiovascular • Glomerulonephritis • Hematological Disorders • Nephrology • Renal Disease • Thrombosis

Inhibition of neutrophil extracellular traps alleviates blood-brain barrier disruption and cognitive dysfunction via Wnt3/β-catenin/TCF4 signaling in sepsis-associated encephalopathy. (PubMed, J Neuroinflammation) - "Our results suggest that inhibition of NETs may protect BBB permeability and cognitive function through the Wnt3/β-catenin/TCF4 signaling pathway in the context of CLP-induced SAE, which provides a promising strategy for SAE therapy."

Journal • Cardiovascular • CNS Disorders • Cognitive Disorders • Infectious Disease • Inflammation • Septic Shock • Vascular Neurology • CDH5 • OCLN • TCF4 • WNT3

PADI4 facilitates stem-like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma. (PubMed, Clin Transl Med) - "The role of citrullinization in cisplatin resistance of OSCC. PADI4 citrullinate of PRMT2 and stabilize PRMT2. PADI4 citrullinate of PRMT2 promoting the transcription of IDs family (ID1, ID2 and ID3) via histone arginine methylation. PADI4 citrullinated PRMT2 affected the combination of PRMT2 and USP7. PADI4 citrullinate of PRMT2 at R312 site. PADI4 inhibitor GSK484 can affect the stemness of OSCC and cisplatin resistance."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Oral Cancer • Squamous Cell Carcinoma • ID2 • PRMT2 • USP7

PAD4 Inhibitor Therapy Prevents NETs and Improves Neurological Deficits Resulting From Subarachnoid Hemorrhage (AAN 2025) - "The PAD4 inhibitor, GSK484, has been shown to improve recovery in SAH-aged mice and may be a viable therapy for positive outcomes in SAH animals. Based on the results, significant recovery in behavioral outcomes is seen, along with a decrease in damaged tissue observed from the infarct volume between days. For future directions, anti-neutrophil therapeutics will be tested."

Hematological Disorders • Inflammation • Subarachnoid Hemorrhage