GSK4024484 / GSK - LARVOL DELTA

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

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...These findings demonstrate the crucial role of PAD4-mediated macrophage migration in tubulointerstitial injury of DKD.*. .*"

Chronic Kidney Disease • Diabetic Nephropathy • Nephrology • Renal Disease

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

Caspase-12 Exhibits Non-Redundant Functions in Response to Endoplasmic Reticulum Stress to Promote GSDMD-Mediated NETosis, Leading to Thoracic Aortic Dissection. (PubMed, Transl Res) - "The ER stress/GSDMD/NETosis signaling pathway provides a potential therapeutic target for the prevention and treatment of TAD."

Journal • Inflammation • CASP1 • CASP12 • CASP4

Activated NETosis of bone marrow neutrophils up-regulates macrophage osteoclastogenesis via cGAS-STING/AKT2 pathway to promote osteoporosis. (PubMed, Exp Cell Res) - "Finally, we found in vivo NETs-clearance through GSK484 significantly inhibited osteoclastogenesis and attenuated osteoporosis of OVX mice. Our study highlights the role of neutrophil NETosis in activating osteoclastogenesis and bone resorption of postmenopausal osteoporosis, thereby providing novel targets for bone loss treatment."

Journal • Inflammation • Osteoporosis • Rheumatology • AKT2 • STING

Bletilla striata polysaccharides alleviate ARDS by inhibiting NETs-induced pyroptosis in pulmonary alveolar macrophage through the PAD4 pathway. (PubMed, Int J Biol Macromol) - "The attenuating effect of BSP was weakened when the GSK484 was introduced to ARDS mice, suggesting the involvement of PAD4 in BSP's mechanism of action. The results demonstrated that BSP has the potential to modulate neutrophil/macrophage homeostasis via the PAD4 pathway, leading to a reduction in NETs levels and alleviation of NETs-induced pyroptosis in alveolar macrophages, alleviating ARDS."

Journal • Acute Respiratory Distress Syndrome • Cardiovascular • Hematological Disorders • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • Thrombosis

Intestinal neutrophil extracellular traps promote gut barrier damage exacerbating endotoxaemia, systemic inflammation and progression of diabetic retinopathy in type 2 diabetes. (PubMed, Diabetologia) - "Severity of diabetic retinopathy and DME were associated with peripheral neutrophilia, gut barrier dysfunction and endotoxaemia in the human participants. db/db mice exhibited intestinal neutrophilia, specifically stem-like pre-neutrophils, which was associated with elevated NETosis and decreased levels of vascular reparative cells. Chronic inhibition of NETosis in db/db mice reduced intestinal senescence and NETs in the retina. These changes were associated with reduced endotoxaemia and an anti-inflammatory bone marrow milieu with retention of pre-neutrophils in the bone marrow and increased gut infiltration of myeloid angiogenic cells. Collectively, PAD-4i treatment decreased gut barrier dysfunction, restoring physiological haematopoiesis and levels of haematopoietic vascular reparative cells."

Journal • Diabetes • Diabetic Macular Edema • Diabetic Retinopathy • Gastrointestinal Disorder • Hematological Disorders • Infectious Disease • Inflammation • Macular Edema • Metabolic Disorders • Ophthalmology • Retinal Disorders • Type 2 Diabetes Mellitus

ACSL1 Aggravates Thromboinflammation by LPC/LPA Metabolic Axis in Hyperlipidemia Associated Myocardial Ischemia-Reperfusion Injury. (PubMed, Adv Sci (Weinh)) - "Finally, ACSL1 knockdown or NETs release inhibitor (DNase I or GSK484) significantly alleviated mIRI in mice. These findings highlight ACSL1 and NETosis as potential key targets for preventing mIRI and underscore the lipid peroxidation in the mechanisms of ACSL1-mediated thromboinflammation."

Journal • Cardiovascular • Dyslipidemia • Genetic Disorders • Inflammation • Metabolic Disorders • Myocardial Infarction • Myocardial Ischemia • Obesity • Reperfusion Injury • ACSL1

Citrullination at the N-terminal region of MDM2 by the PADI4 enzyme. (PubMed, Protein Sci) - "Isothermal titration calorimetry (ITC) in the absence and presence of GSK484, an enzymatic PADI4 inhibitor, indicated that this compound blocked binding of the peptides to the enzyme...The kinetic dissociation rates, koff, measured by biolayer interferometry (BLI), were always one-order of magnitude faster for the citrullinated peptides than for the wild-type ones. Taken together, all these findings indicate that MDM2 is a substrate for PADI4 and is prone to citrullination in the identified (and specific) positions of its N-terminal region."

Journal • Oncology • Targeted Protein Degradation • TP53

C5a/C5aR regulates Th1/Th2 imbalance in sepsis-associated lung injury by promoting neutrophil activation to increase PAD4 expression. (PubMed, Ann Med) - "Additionally, GSK484 intervention on Th1 cell phenotype further affected lung epithelial cell injury. In summary, we revealed the mechanism of C5a/C5aR-induced PAD4 upregulation via neutrophil activation in sepsis-associated lung injury, causing a Th1/Th2 imbalance and lung injury, providing a novel approach for sepsis-associated lung injuries treatment."

Journal • Infectious Disease • Inflammation • Respiratory Diseases • Septic Shock • IL10 • IL1B • IL4 • IL6 • SDC1

GSK484, a PAD4 inhibitor, improves endothelial dysfunction in mice with sepsis-induced lung injury by inhibiting H3Cit expression (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "GSK484 treatment effectively suppresses H3Cit expression in septic mice to ameliorate sepsis-induced endothelial dysfunction."

Journal • Preclinical • Infectious Disease • Respiratory Diseases • Septic Shock • CDH5 • ESM1 • IL1B • IL6 • TJP1

Lenvatinib-activated NDUFA4L2/IL33/PADI4 pathway induces neutrophil extracellular traps that inhibit cuproptosis in hepatocellular carcinoma. (PubMed, Cell Oncol (Dordr)) - "Our study revealed that lenvatinib-induced NETs inhibited the cuproptosis of HCC cells, suggesting that targeting the IL33/PADI4/NET axis represents a promising therapeutic strategy for ameliorating lenvatinib resistance in HCC."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • ELANE • FDX1 • GPX4 • IL33 • NDUFA4L2 • PADI4

Ferroptosis Induces gut microbiota and metabolic dysbiosis in Collagen-Induced arthritis mice via PAD4 enzyme. (PubMed, Gene) - "Erastin, a known ferroptosis agonist, significantly increased the relative abundance of pro-inflammatory bacteria such as Proteobacteria while reducing beneficial taxa like Firmicutes and Bacteroidetes...Co-treatment with GSK484, a PAD4 inhibitor, reversed these effects, restoring microbial homeostasis and reducing joint inflammation. This study suggests that ferroptosis-mediated PAD4 activity contributes to RA pathogenesis by disrupting the gut-joint axis, providing novel insights into potential therapeutic targets for RA. Our results highlight the intricate interplay between immune-mediated cell death, gut microbiota, and systemic inflammation, emphasizing the importance of ferroptosis as a therapeutic target in mitigating RA progression."

Journal • Preclinical • Immunology • Inflammation • Inflammatory Arthritis • Metabolic Disorders • Rheumatoid Arthritis • Rheumatology

Sorafenib-induced macrophage extracellular traps via ARHGDIG/IL4/PADI4 axis confer drug resistance through inhibiting ferroptosis in hepatocellular carcinoma. (PubMed, Biol Direct) - "Our study concludes that sorafenib-induced METs inhibit the ferroptosis of tumor cells, suggesting that targeting the IL4/PADI4/METs axis in HCC could reduce or prevent sorafenib resistance."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • ELANE • GPX4 • IL4

The vacuolar anti-Pseudomonal activity of neutrophil primary granule peptidyl-arginine deiminase enzymes. (PubMed, Front Immunol) - "In phagosomal killing assays, inclusion of the PAD2 inhibitor, AFM-30a, or PAD4 inhibitor, GSK484, significantly increased survival of P. aeruginosa (AFM-30a, p = 0.05; and GSK484, p = 0.0079). Results indicate that PAD2 and PAD4 possess antimicrobial activity and are directly involved in the neutrophil antimicrobial processes. This study supports further research into the development of PAD-based antimicrobials."

Journal • Rheumatology • ELANE

Parvovirus B19 Infection Is Associated with the Formation of Neutrophil Extracellular Traps and Thrombosis: A Possible Linkage of the VP1 Unique Region. (PubMed, Int J Mol Sci) - "The NETosis was observed in the dHL-60 cells treated with rabbit anti-B19V-VP1u IgG and was inhibited in the presence of either 8-Br-cAMP or CGS216800 but not GSK484...Accordingly, a significantly larger thrombus was observed in a venous stenosis-induced thrombosis mouse model treated with PMA, human aPLs IgG, rabbit anti-B19V-VP1u IgG, and human anti-B19V-VP1u IgG, respectively, along with significantly increased amounts of Cit-H3-, MPO- and CRAMP-positive infiltrated neutrophils in the thrombin sections. This research highlights that anti-B19V-VP1u antibodies may enhance the formation of NETosis and thrombosis and implies that managing and treating B19V infection could lower the risk of thrombosis."

Journal • Cardiovascular • Genetic Disorders • Hematological Disorders • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain • Systemic Lupus Erythematosus • Thrombosis • MPO

Von Willebrand factor exacerbates heart failure through formation of neutrophil extracellular traps. (PubMed, Eur Heart J) - "This study established the role of a novel VWF-SLC44A2-NET axis in regulating mitochondrial homeostasis and function, leading to cardiac apoptosis and contributing to HF pathogenesis. Targeting this axis may offer a potential therapeutic approach for HF treatment."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • Metabolic Disorders • TLR4

G-CSF Induces Neutrophil Extracellular Traps Formation and Promotes Ovarian Cancer Peritoneal Dissemination. (PubMed, J Leukoc Biol) - "The association between NETs and peritoneal dissemination was explored, and model mice were treated with the peptidylarginine deiminase 4 (PAD4) inhibitor GSK484 to assess antitumor efficacy...In conclusion, G-CSF was associated with intra-abdominal NETs formation and increased peritoneal dissemination. NETs represent potential therapeutic targets for ovarian cancer, particularly in patients with neutrophilia."

Journal • Oncology • Ovarian Cancer • Solid Tumor • CSF3

Immobilized PAD4 enzyme on magnetic nanoparticles for screening natural inhibitors from traditional Chinese medicines. (PubMed, Talanta) - "The inhibitory activity of the immobilized PAD4 was assessed using two known PAD4 inhibitors GSK484 and BB-Cl-amidine...The IC50 values of Caryophylli Flos extracts for MNP@GA@PAD4 and free PAD4 were determined as 48 and 32 μg/mL, respectively. For the first time, this study proposed a method to immobilize PAD4 on magnetic materials, and developed a rapid, reusable and feasible strategy to screening natural PAD4 inhibitors from TCMs."

Journal • Alzheimer's Disease • CNS Disorders • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

Targeting Post-Translational Protein Modifications As A Novel Therapeutic Strategy For Diffuse Midline Glioma. (EACR 2024) - "The project aims at investigating therapeutic efficacy by targeting PAD-mediated citrullination in DMG.Material and Methods DMG patient-derived RA055 and SU-DIPGXVII cells were treated with a range of PAD inhibitors including Cl-amidine, BB-Cl-amidine, CAY10723, GSK484 and our novel compound in development, JBD-1 with cytotoxicity and colony formation assays performed to determine the pre-clinical efficacy of the compounds...In addition, PAD isoform-specific activity assays and CRISPR/Cas9-mediated PAD-knockout DMG models are being used to identify the PAD isoforms affecting DMG tumorigenesis. Furthermore, mass spectrometry will be employed to investigate how pharmacological and genetic targeting of PADs impact protein citrullination as well as the related signalling pathways involved in DMG tumour metabolism and growth.Conclusion Our results show that protein citrullination potentially plays a critical role in DMG tumorigenesis and targeting PAD-mediated citrullination..."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor