GSK4024484 / GSK - LARVOL DELTA

Platelet peptidylarginine deiminase 4 is not essential for platelet function in homeostasis or fibrosis during normal aging. (PubMed, J Thromb Haemost) - "Collectively, these findings suggest that non-platelet sources of PAD4 are likely driving age-related cardiac fibrosis and provide supporting evidence that PAD4 inhibition to combat excessive NET formation in disease is unlikely to negatively impact platelet function."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology

Mechanisms of Bronchial Smooth Muscle Cell Regulation by Allergic Bronchopulmonary Aspergillosis-Derived Eosinophil Extracellular Traps (ERS 2026) - "Additionally, the effect of the PAD4 inhibitor GSK 484 on EETs formation was assessed...Histones are identified as one of the primary components responsible for the toxic effects of EETs. This pattern of destructive remodeling may directly contribute to the formation of central bronchiectasis in ABPA patients."

Allergic Bronchopulmonary Aspergillosis • Bronchiectasis • Respiratory Diseases • MMP1 • RHOA

Neutrophil NETosis promotes antibiotic tolerance to Pseudomonas aeruginosa in a cystic fibrosis airway model (NACFC 2026) - "Consistent with this, inhibition of NETosis with GSK484 sensitized P. aeruginosa to tobramycin... These findings identify NETosis as a contributor to antibiotic tolerance in a CF-like airway environment. Rather than enhancing bacterial clearance, neutrophil responses to aggregated P. aeruginosa can promote survival during antibiotic treatment. Targeting NETosis may therefore represent a therapeutic strategy to improve antibiotic efficacy in chronic CF airway infection."

Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Respiratory Diseases

Sustained neutrophil extracellular traps cause fracture nonunion. (PubMed, Sci Transl Med) - "Therapeutically, the inhibition of NET formation with the Pad4 inhibitor GSK484 or the promotion of NET clearance with dornase alfa (recombinant DNase1) accelerated bone repair and prevented nonunion in preclinical models. These findings identify sustained NETs as a disruptor of fracture healing and a potential target for enhancing bone regeneration."

Journal • Inflammation • Musculoskeletal Diseases • Orthopedics

Targeting peptidylarginine deiminases 2 and 4 in diabetic kidney disease: mechanistic rationale and preclinical evidence. (PubMed, Biochem Pharmacol) - "We appraise the isoform-selective inhibitor landscape, candidate pharmacodynamic biomarkers, and translational barriers. In summary, PAD inhibition should therefore be framed as a mechanistically distinct, still-preclinical adjunct to the KDIGO 2024 standard of care, with its renal potential depending on isoform-resolved human data and pharmacokinetic characterization in chronic kidney disease."

Journal • Preclinical • Review • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Immunology • Infectious Disease • Inflammation • Inflammatory Arthritis • Nephrology • Oncology • Renal Disease • Rheumatoid Arthritis • Rheumatology • Septic Shock

P. gingivalis activates the NADPH/PAD4 axis to drive macrophage extracellular trap formation and alveolar bone loss in periodontitis. (PubMed, Int Immunopharmacol) - "P. gingivalis promotes the MET-like formation through the NADPH/PAD4 axis, thereby amplifying local inflammation and alveolar bone loss in periodontitis."

Journal • Dental Disorders • Inflammation • Osteoporosis • Periodontitis

PAD4 inhibitor GSK484 alleviates doxorubicin-induced myocardial fibrosis by modulating profibrotic, inflammatory and apoptotic signaling pathways in mice. (PubMed, Eur J Pharmacol) - "Findings show that PAD4 inhibition by GSK484 is associated with reduced fibrosis in DOX-induced cardiomyopathy, accompanied by changes in key inflammatory and profibrotic signaling markers. While the underlying mechanisms remain unclear, findings support further investigation of PAD4 inhibition as a potential therapeutic strategy for fibrotic cardiac diseases."

IO biomarker • Journal • Preclinical • Cardiomyopathy • Cardiovascular • Fibrosis • Heart Failure • Immunology • Inflammation • BAX • BCL2 • CASP9 • IL6 • MMP2 • MMP9 • SMAD7

Neutrophil Extracellular Traps Exacerbate UVB-Induced Photodamage in HaCaT Cells and Mouse Skin via CCDC25/MAPK Pathway. (PubMed, Aging Cell) - "Mice were treated with GSK484 (PAD4 inhibitor) and subjected to RNA-sequencing to explore the mechanism by which NETs promote inflammation and apoptosis...However, this activity was suppressed and cellular status was restored following CCDC25 knockdown. Collectively, NETs exacerbate skin photodamage by activating the p-JNK/JNK pathway via CCDC25, leading to HaCaT cell apoptosis, inhibition of cell viability, and the release of inflammatory cytokines."

Journal • Preclinical • Dermatology • Inflammation • CCDC25 • RASGRF1

GSK484 attenuates placental endothelial injury and improves gestation outcome in rats with preeclampsia by inhibiting PAD4-mediated neutrophil extracellular traps formation. (PubMed, Eur J Pharmacol) - "We conclude that GSK484 exerts a protective effect on rat PE mainly via inhibiting PAD4-mediated placental NETs formation, and ultimately improves maternal placental microvascular injury and benefits the pregnancy outcomes including mother and offspring. The study suggests that GSK484 may have the potential to be an effective drug in the treatment of PE."

Journal • Preclinical • Cardiovascular • Gynecology • Hypertension • Renal Disease • FLT1 • MPO

A Study to Investigate the Safety of GSK4024484 in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=123 | Completed | Sponsor: GlaxoSmithKline | Recruiting ➔ Completed

Trial completion • Infectious Disease • Malaria

Pipa Qingfei Yin Ameliorates Acne Inflammation in Mice via Suppressing Neutrophil Extracellular Traps. (PubMed, Microbiol Immunol) - "In vitro (keratinocytes/neutrophils) and in vivo (C57BL/6 mice) acne models were established using Cutibacterium acnes and treated with PPQFY, DNase I, or GSK484 (NET inhibitors)...These effects were comparable to those of NET inhibitors. PPQFY ameliorates Cutibacterium acnes-induced acne in mice by regulating NETs, providing a novel mechanistic basis for its clinical use and identifying NETs as a potential therapeutic target for acne."

Journal • Preclinical • Acne Vulgaris • Dermatitis • Dermatology • Dermatopathology • Inflammation • IL1B • ITGAM • PADI4 • TNFA

CSF2 drives radiation-induced lung injury by eliciting PADI4-high pathogenic neutrophils. (PubMed, J Transl Med) - "This study delineates an epithelial-myeloid damage-response circuit in RILI and identifies CSF2-driven PADI4 activation in pathogenic neutrophils as a therapeutically actionable mechanism."

Journal • Respiratory Diseases • CSF2

Targeting the NETs-PPIA Axis: A Novel Therapeutic Strategy to Suppress Pathological Synovial Angiogensis in Rheumatoid Arthritis (EULAR 2026) - "Its functional role was validated using the inhibitor Cyclosporin A (CsA)...3) In CIA mice, inhibition of NETs (via GSK484) or PPIA (via CsA) significantly reduced synovial angiogenesis and mitigated bone erosion, with efficacy correlating with reduced NETs deposition...Fig.2. Pro-angiogenic protein PPIA is carried by NETs in rheumatoid arthritis synovium."

Immunology • Inflammatory Arthritis • Osteoarthritis • Rheumatoid Arthritis • Rheumatology • CD31 • PECAM1 • PPIA

Peptidylarginine deiminase 4-mediated citrullination in human disease: molecular mechanisms and therapeutic targeting. (PubMed, Front Pharmacol) - "Drug development has progressed from early irreversible inhibitors, including Cl-amidine and F-amidine, to more selective reversible compounds such as GSK484 and GSK199, as well as newer orally available candidates such as JBI-589 and JBI-1044. Emerging approaches, including allosteric ligands, cyclic peptides, and functional antibodies, continue to broaden the PAD4-targeting landscape. In this review, we summarize the molecular basis of PAD4-mediated citrullination, examine its contributions to major disease settings, evaluate current and emerging PAD4-directed therapies, and discuss the key challenges that must be addressed for successful clinical translation."

Journal • Review • Atherosclerosis • Cardiovascular • Hematological Disorders • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Oncology • Rheumatoid Arthritis • Rheumatology • Septic Shock • Systemic Lupus Erythematosus • Thrombosis

Neutrophil extracellular traps drive tubulointerstitial fibrosis via the coiled-coil domain-containing protein 25 (CCDC25)-Yes-associated protein 1 (YAP1) axis-mediated autophagy regulation. (PubMed, Br J Pharmacol) - "Our study provides the first evidence that NETs exacerbate CKD-TIF by enhancing fibroblast autophagy via the CCDC25-YAP1 axis, highlighting the NETs inhibitor GSK484 as a promising therapeutic candidate."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • CCDC25 • RASGRF1 • YAP1

Forsythia suspensa accelerates wound healing by inhibiting neutrophil extracellular traps and activating Wnt/β-catenin via forsythoside A. (PubMed, Phytomedicine) - "LQ and forsythoside A promote skin wound healing by coordinately regulating NET-mediated inflammation and Wnt/β-catenin signaling-mediated cell proliferation, thereby highlighting their potential as therapeutic agents in regenerative medicine."

Journal • Inflammation • Thermal Injury

Extracellular traps from myeloid cells as therapeutic targets in traumatic heterotopic ossification. (PubMed, Sci Transl Med) - "Pharmacological facilitation of ET clearance by dornase alfa, a US Food and Drug Administration-approved recombinant DNase1, or inhibition of ETs by the PADI4 inhibitor GSK484, resulted in inhibition of traumatic HO formation in mice without adversely affecting systemic bone remodeling. Together, our clinical and experimental findings demonstrate that traumatic HO is mediated by targetable neutrophil-dependent mechanisms, with altered ET formation contributing to these effects."

Journal • Musculoskeletal Diseases • DNASE1L3

Reengineered Albumin-Paclitaxel Nanoparticles Remodeling Tumor Cell Death Pathways for Prevention of Chemotherapy-Induced Breast Cancer Metastasis. (PubMed, ACS Nano) - "In this investigation, we engineered a tumor-responsive nanoparticle platform (RAPG) capable of codelivering PTX, the Padi4 inhibitor GSK484, and a RAGE antagonist peptide (RAP). In both in vitro and in vivo assessments, RAPG attenuated epithelial-mesenchymal transition markers and reduced tumor invasiveness, circulating tumor cells, and lung metastasis, while enhancing treatment efficacy and prolonging survival. This study presents a promising strategy to counteract chemotherapy-induced metastasis in TNBC through concurrent inhibition of Padi4-mediated histone citrullination and RAGE/ERK signaling."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CTCs

ASGR1 induces neutrophil extracellular traps formation to exacerbate sepsis-induced myocardial injury and cardiac dysfunction through SLC7A11 ubiquitination. (PubMed, Clin Sci (Lond)) - "Anti-Ly6G and GSK484 deplete neutrophils and neutrophil extracellular traps (NETs), alleviating myocardial injury and cardiac dysfunction, and promoting survival of LPS-challenged mice...ASGR1 acts as a bridge to transfer the attached ubiquitin to SLC7A11 and facilitates K48-linked ubiquitination degradation of SLC7A11 by SOCS2. Our findings suggest that ASGR1 is a principal indicator of SIMD by inducing NET formation. In addition, the regulation of NET formation could be a potential treatment for SIMD."

Journal • Critical care • Infectious Disease • Septic Shock • Targeted Protein Degradation • SLC7A11 • SOCS2

Tumor Egfl6 is a new driver of neutrophil extracellular traps (NETs) in ovarian cancer (IMMUNOLOGY 2026) - "Our findings identify EGFL6 as a previously unrecognized tumor-derived driver of NETosis, contributes to immunosuppression in OvCa. NETs directly impair NK cell functions in Egfl6+ tumors, while NETosis inhibition with GSK484 partially restores anti-tumor immunity by enhancing NK cell cytotoxic and reprogramming myeloid cells. These data support targeting NETosis as a therapeutic approach to enhance current therapies in OvCa."

Oncology • Ovarian Cancer • Solid Tumor • CD86 • CXCL8 • EGF • ELANE • KLRC1 • KLRG1 • LAMP2 • TP53

A Specific Subset of Low-Density Neutrophils Aggravates Endothelial Denudation via NET-Mediated ANXA1 Sequestration: Implications for Plaque Erosion (IMMUNOLOGY 2026) - "Mechanistic pathways were investigated in an ApoE−/− mouse model of PE and human aortic endothelial cell (HAEC) co-cultures, utilizing CXCR2 inhibitors (AZD-5069) and NET inhibitors (GSK484). A distinct, pro-inflammatory LDN subset was significantly expanded in PE-ACS patients, correlating strongly with endothelial microvesicles and thrombus burden. PE LDNs constitute a pathogenic neutrophil subset that drives PE-ACS. They are recruited via the CXCL1/2-CXCR2 axis and promote endothelial denudation and thrombosis by releasing NETs that compromise ANXA1-mediated membrane repair. Targeting the PE LDN-NET-ANXA1 axis represents a potential therapeutic strategy for PE."

Acute Coronary Syndrome • Cardiovascular • Hematological Disorders • Thrombosis • ANXA1 • APOE • CXCL1 • MME

Roles of peptidylarginine deiminase (PAD) and protein citrullination in viral infections. (PubMed, Front Microbiol) - "We further compare the divergent strategies employed by DNA and RNA viruses in leveraging PAD-mediated citrullination and summarize the therapeutic potential of PAD inhibitors, such as GSK484 and Cl-amidine, in antiviral interventions. Additionally, demethoxycurcumin (DMC), as the only identified selective small-molecule activator of PAD2 to date, provides a valuable tool for investigating the role of PAD2-mediated citrullination in viral infection. Finally, we discuss current research limitations and propose future directions aimed at deciphering the complex virus-PAD-host axis, with the ultimate goal of informing the development of novel antiviral therapeutics."

Journal • Review • Infectious Disease

Reprogramming Tumor-Associated Neutrophils to Enhance Radio-Immunotherapy. (PubMed, Adv Mater) - "To reprogram these RT-recruited tumor-associated neutrophils (TANs), we develop injectable hydrogel microspheres (HMPs) co-loaded with a TLR4 agonist (lipopolysaccharide) and a PAD4 inhibitor (GSK484)...In murine tumor models, the combination of RT and L/G@HMPs triggers robust innate and adaptive immune responses, marked by substantial accumulation of N1-polarized TANs and CD8+ T cells within tumors, leading to potent tumor eradication. This study presents a hydrogel-based strategy that concurrently modulates neutrophil lifespan, phenotype, and NETs, thereby transforming tumor-promoting neutrophils into anti-tumor allies for enhanced radio-immunotherapy."

Journal • Oncology • CD8 • TLR4

Neutrophil Extracellular Traps Aggravate Injury in Complement-Mediated Thrombotic Microangiopathy. (PubMed, J Am Soc Nephrol) - "Levels of NETs biomarkers increased in complement-mediated TMA and drove multi-organ injury by shedding CD59 from HRGECs to enhance complement activation and participate in coagulation activation."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Renal Disease • Thrombosis • CD59

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