setanaxib (GKT831) / Calliditas, National Institutes of Health - LARVOL DELTA

Immune-driven biotransformation of gold nanosheets by human primary neutrophils. (PubMed, Nanoscale Adv) - "Pharmacological dissection using inhibitors of myeloperoxidase (4-aminobenzoic acid hydrazide, 4-ABAH), NADPH oxidase NOX1/4 (Setanaxib; GKT137831) and 1-methylpropyl 2-imidazolyl disulfide; thioredoxin-1 (PX12) demonstrates that degradation requires convergence of parallel oxidative routes (MPO/HOCl and Fenton-like) with Trx-1-mediated thiol capture of Au+ as Au-S-Trx...Transcriptional profiling further reveals coupling between oxidative burst activity and inflammatory signalling. These findings redefine the biological stability of gold nanostructures under physiologically relevant inflammatory conditions."

Journal • MPO

Epigenetically Regulated NOX4/NRF2 Axis Mediates PM2.5-Induced Ferroptosis and Inflammatory Response in Membranous Nephropathy. (PubMed, J Appl Toxicol) - "Notably, pretreatment with GKT137831 or ferrostatin-1 attenuated the PM2.5-mediated reduction in cell viability and prevented the activation of ferroptosis and pro-inflammatory phenotypes in PAN-stimulated MPC5 cells. In conclusion, PM2.5 promotes ferroptosis and inflammation through an epigenetically regulated NOX4/NRF2 axis, thereby exacerbating renal injury in MN."

Journal • Glomerulonephritis • Hematological Disorders • Inflammation • Renal Disease • DNMT1 • NOX4

Nox1/4 inhibitor Setanaxib treatment ameliorates cardiac function in mouse models of Duchenne Muscular Dystrophy. (PubMed, Mol Ther) - "Further transcriptomic analysis of the hearts treated with Setanaxib revealed an enrichment in genes associated with fatty acid metabolism, oxidative phosphorylation, and protein binding, while genes related to epithelial-mesenchymal transition were downregulated. Collectively, these findings suggest that oxidative stress plays a key role in development of myocardial fibrosis and heart failure caused by dystrophin deficiency and suggest that Nox1/4 inhibitor treatment could be a novel therapy to treat DMD-associated cardiomyopathy."

Journal • Preclinical • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Heart Failure • Immunology • Muscular Dystrophy • NOX4

NOX4 promotes cardiomyocyte ferroptosis-related injury in septic cardiomyopathy in associated with mitochondrial dysfunction and impaired NRF2 nuclear translocation. (PubMed, Int J Biol Macromol) - "In the cecal ligation and puncture mouse model, pharmacological inhibition of NOX4 with Setanaxib improved survival and cardiac function, reduced myocardial injury biomarkers, alleviated histopathological damage, and partially reversed the dysregulation of ferroptosis-related markers...In addition, candidate compounds identified from the HERB database and evaluated by molecular docking and molecular dynamics simulations were predicted to exhibit stable binding features with NOX4. Collectively, these findings support a model in which NOX4 contributes to ferroptosis-related injury in septic cardiomyopathy in association with mitochondrial dysfunction and impaired NRF2-dependent antioxidant signaling."

Journal • Cardiomyopathy • Cardiovascular • Infectious Disease • Metabolic Disorders • Respiratory Diseases • Septic Shock • ACSL4 • GPX4 • NOX4 • SLC7A11

Procontractile influence of ROS, produced by NADPH oxidase, is greater during contraction induced by thromboxane A2 than α1-adrenoceptor activation. (PubMed, Free Radic Res) - "The effect of VAS2870 persisted in the presence of LTCC (L-type voltage-gated Ca2+ channels) blocker nimodipine during U46619-induced, but not methoxamine-induced contraction...NOX2 inhibitor GSK2795039 (10 μM), but not NOX1/4 inhibitor GKT137831, weakened significantly both methoxamine- and U46619-induced contraction...Thus, procontractile influence of ROS, produced by NADPH oxidase (mainly, by NOX2), is greater during contraction induced by thromboxane A2 than α1-adrenoceptor activation in rat mesenteric arteries. Such influence is realized by activation of LTCC when α1-adrenoceptors are stimulated and by activation of protein kinase C when thromboxane A2 receptors are stimulated."

Journal • NOX4

Basal release of 6-cyanodopamine from rabbit isolated aorta and its modulation of vascular reactivity. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Rabbit aorta released significant amounts of 6-CYD, which were largely reduced either by endothelium removal or pre-incubation with the NOX1/4 inhibitor GKT137831 (1 µM), whereas the nitric oxide (NO) synthase inhibitor L-NAME (100 µM) and the voltage-gated sodium channel blocker tetrodotoxin (TTX, 1 µM) had no significant effect. In ET-1-pre-contracted rings, 6-CYD (1 nM-10 µM) produced concentration-dependent relaxations that were significantly reduced by endothelium removal and L-NAME (100 µM), as well as by the soluble guanylyl cyclase (sGC) inhibitors ODQ (100 µM) and methylene blue (10 µM). In conclusion, these findings identify vascular endothelium as a source of 6-CYD and indicate this catecholamine as a novel endogenous modulator of vascular tone, acting through a dual mechanism, namely, potentiating vasoconstriction and producing NO/sGC-dependent vasorelaxation."

Journal • Preclinical • EDN1

Nox4 mediates chondrocyte senescence and cartilage degradation in post-traumatic osteoarthritis via the ROS/p38MAPK signaling pathway. (PubMed, Int Immunopharmacol) - "Conversely, pharmacological inhibition of Nox4 with GKT137831 or scavenging reactive oxygen species (ROS) with N-acetylcysteine (NAC) alleviated these effects, suggesting that Nox4 contributes to chondrocyte senescence potentially via ROS accumulation. Furthermore, Nox4-induced p38MAPK activation was closely associated with increased senescence and ECM degradation, and these pathological changes were reversed by the p38MAPK inhibitor SB203580. These findings highlight the Nox4-p38MAPK axis as acritical driver of OA progression and suggest that targeting this pathway may offer a promising therapeutic strategy to mitigate cartilage degradation and senescence."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • ACAN • CDKN1A • NOX4

SAFETY AND PRELIMINARY EFFICACY FINDINGS FROM A PHASE 2A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF SETANAXIB IN PATIENTS WITH ALPORT SYNDROME (ISN-WCN 2026) - P1/2 | "The setanaxib group also had a 27% mean UPCR reduction at 4 weeks post dosing versus placebo. There was a 5% mean reduction in eGFR with setanaxib versus placebo at 24 weeks and a 4% reduction at 4 weeks post dosing.Conclusion In patients with Alport syndrome, setanaxib plus background therapy had an acceptable safety profile with a trend towards UPCR reduction after 24 weeks of dosing and at 4 weeks post dosing versus background therapy alone.This abstract was also submitted for the American Society of Nephrology Kidney Week 2025 congress.I have potential conflict of interest to disclose.This study was funded by Calliditas Therapeutics AB DG has received consulting/research funding from: Novartis; Alexion; Calliditas; CSL Vifor; Judo Bio; Alnylam; Sanofi; Apellis; SOBI; Bayer; STADA; Otsuka; Apellis; GSK; Travere; Vera; Boehringer IngelheimI did not use generative AI and AI-assisted technologies in the writing process."

Clinical • P2a data • Fibrosis • Gastroenterology • Genetic Disorders • Hepatology • Immunology • Nephrology

NOX1/4 drives hepatic iron and lipid dysregulation, redox imbalance, and inflammation in ethanol-fed mice. (PubMed, Sci Rep) - "Our findings suggest that NOX1/4 may play a central role in coordinating the interconnected pathogenic processes that drive ALD progression, including iron overload, lipid dysregulation, oxidative stress, and inflammation. Our findings establish Setanaxib, a novel NOX1/4 inhibitor, as a promising multi-target therapeutic strategy for ALD."

Journal • Preclinical • Hematological Disorders • Hepatology • Inflammation • Liver Failure • Metabolic Disorders • GPX4 • SLC7A11 • TFRC

Redox Modulation in Hepatic Fibrosis: Translating NOX1/4 Inhibition to Therapy. (PubMed, Int J Mol Sci) - "Setanaxib is a first-in-class, orally bioavailable, selective dual inhibitor of NOX1 and NOX4 that has progressed to clinical evaluation...The compound also demonstrates favorable pharmacokinetic properties and a good safety profile in patients with PBC, with emerging evidence suggesting meaningful improvements in fatigue and quality of life. Finally, we examine the complex, and sometimes paradoxical, roles of NOX4 in liver pathophysiology, compare the evolving therapeutic landscape with other approaches such as farnesoid X receptor (FXR) agonists, and propose future paradigms integrating artificial intelligence-driven predictive modeling to optimize patient stratification and therapeutic response in this new era of redox-targeted hepatoprotective therapy."

Journal • Review • Fatigue • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Primary Biliary Cholangitis • NOX4 • TGFB1

Plumbagin protects rat cortical neurons from mechanical trauma injury-induced apoptosis by inhibiting NOX4/ROS/p38 MAPK pathway. (PubMed, Avicenna J Phytomed) - "Rat primary cortical neurons were isolated from time-mated pregnant Sprague-Dawley rats and cultured in vitro, and then, randomly divided into control group，trauma group，trauma+GKT137831 (50 μM) group，trauma+PLB (5 μM) group, trauma+PLB (10 μM) group and trauma+PLB (20 μM) group．The influence of PLB on rat primary cortical neuron viability and morphology was evaluated after mechanical injury...Furthermore, PLB counteracted the mechanical injury-mediated apoptosis (p<0.01) and inhibited the expression of NOX4 protein and p38 MAPK phosphorylation in cortical neurons compared with the trauma group (p<0.01). The present findings illustrate that PLB can alleviate mechanical trauma injury-induced apoptosis by inhibiting the NOX4/ROS/p38 MAPK pathway in primary cortical neurons."

Journal • Preclinical • CNS Disorders • Vascular Neurology • NOX4

Selective Head Cooling and NOX Inhibition Protect the Blood-Brain Barrier in Neonatal Epilepsy. (PubMed, Antioxidants (Basel)) - "Pharmacological inhibition of NOX with setanaxib (5 mg/kg) or sulforaphane (0.4 mg/kg) also prevented BBB disruption during normothermia...These findings identify endothelial NOX as a key mediator of seizure-induced BBB injury and demonstrate that both NOX inhibition and selective head cooling effectively preserve cerebrovascular integrity. Combined hypothermic and antioxidant therapy may offer a promising strategy to prevent cerebrovascular injury and BBB damage in neonatal epilepsy."

Journal • CNS Disorders • Epilepsy • MCAM • PTPRC • SLC2A1 • TNFA

Inhibition of NOX4 attenuates muscle damage and mitochondrial dysfunction in inflammatory myopathy. (PubMed, Arthritis Res Ther) - "We showed that NOX4 is associated with muscle damage in IIM and suggest that its inhibition may have novel therapeutic effect for mitigating muscle damage and disease progression in IIM."

Journal • Immunology • Inflammation • Metabolic Disorders • Myositis • IFNG • IL6 • MYOD1 • NOX4

Pyraclostrobin induces brain oxidative stress, apoptosis and inflammation through mitochondrial phosphorylation-induced ROS activation of the p38 MAPK pathway. (PubMed, Pestic Biochem Physiol) - "NAC and GKT137831 blocked ROS-mediated MAPK signaling. JC-1 and DHE staining experiments further demonstrate that PY causes mitochondrial dysfunction in the mouse brain and significantly increases ROS production. Collectively, these findings enhance our understanding of the neurotoxic effects of PY pesticide residues and provide a scientific foundation management."

IO biomarker • Journal • CNS Disorders • Inflammation • Metabolic Disorders • Vascular Neurology • BCL2 • CASP3 • CASP8 • CASP9 • IL10 • IL1B • IL6 • TNFA

From RAAS blockade to regenerative medicine: evolving treatment strategies in Alport syndrome. (PubMed, Pediatr Nephrol) - "Adjunctive commercially available metabolic modulators, including SGLT2i, mineralocorticoid receptor antagonists, ezetimibe and GLP-1 receptor agonists, may offer additional kidney protection. Ameliorating therapies being tested in Phase II trials include endothelin receptor antagonists (e.g., atrasentan), dual endothelin receptor antagonist and angiotensin II receptor inhibition (e.g., sparsentan) FXR agonists (e.g., vonafexor), inducers of cholesterol efflux (e.g., VAR200 and R3R01), and NOX1/4 inhibitors (e.g., setanaxib), several of which are currently being evaluated in clinical trials. Novel strategies such as exon skipping, gene editing, and nonsense mutation readthrough (e.g., ELX-02) are advancing toward precision medicine approaches as disease modifying agents targeting the genetic cause of AS...This review summarizes the current landscape of AS classification and treatment, highlighting both standard interventions and experimental therapies. Emphasis is placed..."

Journal • Review • Fibrosis • Gene Therapies • Genetic Disorders • Glomerulonephritis • Immunology • Renal Disease • COL4A5

Mitochondrial Transcriptional-Translational Conflict Contributes to Defective Erythropoiesis and Disease Progression in Splicing Factor Mutant Myelodysplastic Syndromes (ASH 2024) - "We screened ROS scavengers (N-acetylcysteine), NAD+ precursor (Nicotinamide Riboside), integrated stress response inhibitor or ESR inhibitor (ISRIB, 4-Phenylbutyric acid), NADPH oxidase inhibitor (Setanaxib), tropomyosin receptor kinase (TRK) inhibitor (Larotrectinib), and translation-associated drugs (A-484954, 4EGI-1) to test whether they can rescue anemia, but unfortunately all of these drugs failed to improve erythropoiesis of mutated cells. In summary, our findings provide insights into the critical role of mitochondrial transcription and translation in governing erythropoiesis via the mTOR signaling pathway. We propose that SF3B1 mutation cause dysfunctional mitochondria and elevated ESR, leading to aberrant mitochondrial translation and impaired protein synthesis, and suggest rapamycin as a potential therapeutic strategy for MDS patients with SF3B1 mutation to alleviate anemia by inhibiting stress-induced mTOR activation."

Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • ATF4 • CD34 • SF3B1

Safety and Preliminary Efficacy Findings from a Phase 2A Randomized, Double-Blind, Placebo-Controlled Trial of Setanaxib in Patients with Alport Syndrome (KIDNEY WEEK 2025) - P1/2 | "There was a 5% mean reduction in eGFR with seta vs pbo at 24 wks and a 4% reduction at 4 wks post dosing. Conclusion In pts with AS, setanaxib plus background therapy had an acceptable safety profile with a trend towards UPCR reduction after 24 wks of dosing and at 4 wks post dosing vs background therapy alone."

Clinical • Late-breaking abstract • P2a data • Fibrosis • Gastroenterology • Genetic Disorders • Hepatology • Immunology

Basal release of 6-cyanodopamine in human vas deferens, a new endogenous catecholamine that enhances smooth muscle contractility. (PubMed, Eur J Pharmacol) - "Basal release of 6-CYD was quantified by liquid chromatography coupled to tandem mass spectrometry in the absence and presence of either the voltage-gated sodium channel blocker tetrodotoxin or the dual NADPH oxidase NOX1,4 inhibitor GKT137831. The results indicate that epithelium 6-CYD is an endogenous mediator of HEVD contractility. Whether NADPH oxidases are involved in 6-CYD biosynthesis remains to be further investigated."

Journal

Mitochondrial NOX4 Drives Atrial Fibrillation via Redox-Dependent Structural Remodeling and Fibrosis. (PubMed, Free Radic Biol Med) - "Inhibiting NOX4 with Setanaxib reduced AF duration. These findings demonstrate that mitochondrial NOX4 promotes AF not by altering ionic currents or promoting RyR2 leak, but through redox-sensitive fibrotic remodeling. Our results underscore the chamber-specific consequences of oxidative stress and support therapeutic targeting of mitochondrial NOX4 to mitigate atrial remodeling and AF in aging hearts."

Journal • Atrial Fibrillation • Cardiovascular • Fibrosis • Immunology • CAPN2 • NOX4 • POSTN

Genetic and Pharmacological Inhibition of NOX4 Protects Against Rhabdomyolysis-Induced Acute Kidney Injury Through Suppression of Endoplasmic Reticulum Stress. (PubMed, Antioxidants (Basel)) - "We applied renal tubular epithelial cell (RTEC)-specific NOX4 knockout and the NOX4 inhibitor GKT137831 to treat RIAKI in vivo and in vitro...Collectively, these findings demonstrate that genetic and pharmacological suppression of NOX4 protects against RIAKI by reducing ROS generation, boosting antioxidant defense and inhibiting ERS activation. NOX4 inhibition may offer a potential approach for developing new treatment options for RIAKI."

Journal • Acute Kidney Injury • Inflammation • Nephrology • Renal Disease • NOX4

An update on novel investigational agents for the treatment of primary biliary cholangitis. (PubMed, Expert Opin Investig Drugs) - "While ursodeoxycholic acid (UDCA) remains the first-line treatment, up to 40% of patients show an inadequate response...Obeticholic acid (OCA), a farnesoid X receptor agonist, was initially approved but recently lost its marketing authorization in the EU due to an unfavorable risk-benefit balance. Fibrates, particularly bezafibrate and fenofibrate, have shown promising results in improving biochemical markers and reducing pruritus, although they remain off-label. We here focus on new FDA- and EMA-approved therapies, including the PPAR agonists elafibranor and seladelpar, which demonstrate improved biochemical response and, in the case of seladelpar, a significant reduction in pruritus. Additional investigational agents include NOX inhibitors such as setanaxib, IBAT inhibitors like linerixibat and odevixibat, and golexanolone, targeting fatigue through modulation of GABAergic neurotransmission. Despite advances, challenges remain in treatment personalization, access to..."

Journal • Review • Dermatology • Fatigue • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Primary Biliary Cholangitis • Pruritus

Targeting NOX1/4-YAP/TEAD-CD47 Axis Promotes Macrophage Phagocytosis and Potentiates Radiotherapy Antitumor Efficacy in NSCLC (IASLC-WCLC 2025) - "THP-1-derived macrophages were co-cultured with lung tumor cells treated with NOX1/NOX4 inhibitor (GKT137831, GKT)...Conclusions : This study unveils a novel mechanism which regulates basal CD47 expression and radiotherapy-induced CD47 upregulation in tumor cells. Targeting NOX1/NOX4-YAP1/TEAD4 signaling could suppress CD47 expression, resulting in promoting phagocytosis function of macrophages without blood toxicity and improving the anti-tumor efficacy of radiotherapy in NSCLC."

Clinical • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD47 • NOX4 • TEAD4 • YAP1

GSN000400: A Study of Setanaxib Co-Administered With Pembrolizumab in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of Head and Neck (SCCHN) (clinicaltrials.gov) - P2 | N=55 | Completed | Sponsor: Calliditas Therapeutics Suisse SA | Active, not recruiting ➔ Completed

IO biomarker • Trial completion • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CAFs • PD-L1

A Study to Evaluate Setanaxib in Patients With Alport Syndrome (clinicaltrials.gov) - P1/2 | N=19 | Completed | Sponsor: Calliditas Therapeutics AB | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders

Synthetic and semi-synthetic antioxidants in medicine and food industry: a review. (PubMed, Front Pharmacol) - "Nevertheless, some compounds, such as ebselen, edaravone, MitoQ10, and potentially N-acetylcysteine, have shown promising results...One emerging therapeutic strategy involves inhibition of NADPH oxidase (NOX) enzymatic activity, with compounds such as ebselen, S17834, and GKT137831 showing potential across various disease models...Despite extensive research, only a few synthetic antioxidants, such as edaravone, are currently used in clinical practice. Currently, no new antioxidant drugs are expected to receive regulatory approval in the near future."

Journal • Review