selonsertib (GS-4997) / Gilead - LARVOL DELTA

ACSL1 suppresses breast cancer progression by activating ASK1/JNK pathway-mediated autophagy-dependent ferroptosis. (PubMed, Int J Biochem Cell Biol) - "By activating ASK1/JNK pathway-driven, autophagy-dependent ferroptosis, ACSL1 exerts a tumor-suppressive role in breast cancer, underscoring its promise as a therapeutic target."

Journal • Breast Cancer • Oncology • Solid Tumor • ACSL1

Inflammation as a therapeutic target to improve kidney and cardiovascular outcomes. (PubMed, Nat Rev Nephrol) - "Investigational treatments that have targeted inflammation include inhibition of apoptosis signal-regulating kinase-1 (ASK1) by selonsertib, Janus kinase (JAK) 1/2 inhibition with baricitinib, protein kinase C-β (PKCβ) inhibition with ruboxistaurin, nuclear factor erythroid 2-related factor 2 (Nrf2) activation with bardoxolone, phosphodiesterase inhibition with pentoxifylline and monoclonal antibodies against IL-1β and IL-6. Furthermore, proven therapies for CKD, including renin-angiotensin-aldosterone system inhibitors, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid antagonists, possess anti-inflammatory properties that might contribute to their previously established clinical benefits."

Journal • Review • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Inflammation • Nephrology • Renal Disease • CRP • IL1B • IL6 • PRKCB

Eriodictyol targets the ubiquitination/phosphorylation of apoptosis signal-regulating kinase 1 and alleviates pressure-overload induced myocardial fibrosis in mice. (PubMed, Br J Pharmacol) - "ERIO is a safe, effective natural flavonoid with promising preclinical efficacy, suggesting its potential clinical translation for myocardial fibrosis and offering new therapeutic targets to prevent heart failure progression."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Inflammation • Targeted Protein Degradation • TGFB1

SR-A3 Promotes USP18-Mediated deISGylation of STING to Protect Against Myocardial Ischemia-Reperfusion Injury. (PubMed, Adv Sci (Weinh)) - "Treatment with Selonsertib, an ASK1 inhibitor that increased USP18 abundance in our MI/RI model, recapitulated the cardioprotective effects, highlighting the translational potential of targeting this signaling axis. Collectively, our findings uncover a novel SR-A3/USP18/ISG15/STING regulatory pathway governing innate immune activation in MI/RI and position SR-A3 as a promising therapeutic target for ischemic heart disease."

Journal • Cardiovascular • Coronary Artery Disease • Heart Failure • Myocardial Infarction • Myocardial Ischemia • Reperfusion Injury • Targeted Protein Degradation • SCARA3 • STING • USP1 • USP18

Prognostic stratification in a diabetic kidney disease trial using plasma concentrations of soluble tumor necrosis factor receptor 1. (PubMed, Kidney Res Clin Pract) - "Soluble tumor necrosis factor receptor 1 concentration was measured across plasma samples from Joslin cohort and selonsertib trial cohort...We demonstrated the prognostic utility of plasma concentrations of circulating soluble tumor necrosis factor receptor 1 in identifying individuals with diabetic kidney disease at an elevated risk of progressive kidney function decline in a randomized clinical study setting. This data supports previous findings from large observational cohorts and supports the use of this marker as a reliable predictor of disease outcome."

Clinical • Journal • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Glomerulonephritis • Metabolic Disorders • Nephrology • Oncology • Renal Disease • Type 2 Diabetes Mellitus • TNFA

SOX9 knockdown alleviates Aβ1‑42‑induced neuroinflammation by regulating microglial polarization via inactivation of the ASK1/JNK signaling pathway. (PubMed, J Mol Histol) - "Consistently, GS-4997 blocked the pro-inflammatory and neurotoxic effects induced by SOX9 overexpression. SOX9 exacerbates AD neuroinflammation by promoting microglial M1 polarization via the ASK1/JNK signaling axis."

IO biomarker • Journal • Alzheimer's Disease • CNS Disorders • Inflammation • BAX • BCL2 • CASP3 • SOX9

SOS1-RAS-RAF signaling sensitizes platelet responsiveness via GPVI and PAR-1 (ISTH 2026) - "At high convulxin and TRAP-6 concentrations, inhibition of SOS1-RAS interaction, (Bay-293), BRAF (PLX4032) or BRAF dimerization (PLX8394) partially reduced platelet αIIbβ3 integrin activation, P-selectin/CD63 surface expression, aggregation and phosphatidylserine exposure in a dose dependent manner...Synergistic inhibition of convulxin-induced platelet activation and MEK1/2 S217/221 phosphorylation was observed by combined blocking of BRAF and PKC isoforms (GF109203X), P2Y 12 receptor (AR-C69931), PI3K-p110β (TGX-221) and ASK1 (selonsertib), respectively...This project was supported by the German Research Foundation (DFG). DOI*10.1016/j.rpth.2026.105258"

ARAF • CD63 • MAP2K1

Study on mechanism of salt-stir fried Eucommiae Cortex to enhance therapeutic efficacy on renal fibrosis through epithelial-mesenchymal transition (PubMed, Zhongguo Zhong Yao Za Zhi) - "Furthermore, the ASK1 inhibitor Selonsertib significantly downregulated levels of EMT and p38 phosphorylation in NRK-52E cells stimulated by TGF-β. Therefore, SEC can enhance the therapeutic effect on renal fibrosis by inhibiting the EMT process, and its specific mechanism is related to the inhibition of the ASK1/p38 signaling pathway."

Journal • Fibrosis • Immunology • Oncology • FN1 • IL1B • IL6 • SNAI1 • TGFB1 • TNFA • TWIST1 • VIM • ZEB1

Deep contrastive learning framework identifies cell-type-specific drug targets in Alzheimer's disease. (PubMed, Alzheimers Dement (Amst)) - "AlzCL offers a deep contrastive learning framework for discovery of disease-associated genes and drug targets in AD."

Journal • Alzheimer's Disease • CNS Disorders • MAP3K5 • P2RX4 • PRKD1

Design, synthesis, and biological evaluation of FXR/ASK1 dual-target modulators. (PubMed, Beilstein J Org Chem) - "Through the effective functional group splicing strategy, a new dual-target modulator is designed. Compound Z8, which acts on both targets, was found to more potently reduce intracellular lipid droplet accumulation in OA-treated HepG2 cells than the FXR agonist GW4064 and the ASK1 inhibitor selonsertib (GS-4997)."

Journal • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Monocrotaline induces liver injury via TRX1-ASK1-JNK Axis-mediated mitochondrial damage in hepatocytes. (PubMed, Int Immunopharmacol) - "Pretreatment with the ASK1 inhibitor Selonsertib (SEL) attenuated MCT-induced liver injury by suppressing ASK1-JNK activation and preserving mitochondrial integrity. These results indicate that MCT elicits hepatotoxicity via TRX1-ASK1-JNK axis-mediated mitochondrial damage, and that SEL disrupts this cascade, highlighting the therapeutic potential of ASK1 inhibition in PAs-ILI."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Metabolic Disorders

E3 Ubiquitin Ligase TRIM21 Exacerbates Pathological Cardiac Hypertrophy Through ASK1 K63-Linked Polyubiquitination. (PubMed, FASEB J) - "Crucially, the pro-hypertrophic effects of TRIM21 were abrogated by pharmacological inhibition of ASK1 (GS-4997). In conclusion, these findings define a novel TRIM21-ASK1 axis that drives pathological cardiac hypertrophy, highlighting TRIM21 as a promising therapeutic target for hypertrophic heart disease and heart failure."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Ischemia • Targeted Protein Degradation • MAPK8 • TRIM21

Pyrazolopyridine derivatives as potent ASK1 inhibitors: design, synthesis, and biological evaluation. (PubMed, Bioorg Chem) - "In this study, using the clinical candidate drug GS-4997 as a reference structure, a series of pyrazolopyridine-based ASK1 inhibitors were designed and synthesized through a fused-ring cyclization strategy and azacyclic modification of the benzamide aromatic ring...Molecular docking results indicated that compound 20 forms key hydrogen bonds with VAL757 (1.90 Å) and LYS709 (2.27 Å) of ASK1, while its (S)-trifluoropropyl side chain further interacts with LYS688 (2.51 Å). These results demonstrate that compound 20 is a promising lead candidate for the treatment of NASH."

Journal • Metabolic Dysfunction-Associated Steatohepatitis • TNFA

Acetyl-CoA Carboxylase Inhibitors for Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. (PubMed, Pharmaceuticals (Basel)) - "Interventions included firsocostat, clesacostat, and combined regimens with semaglutide, selonsertib, and cilofexor or ervogastat. Dual ACC 1/2 inhibitors reduce hepatic steatosis and ALT levels but do not improve fibrosis. Their consistent association with hypertriglyceridemia raises concerns regarding potential long-term cardiometabolic risks, particularly in NAFLD patients with metabolic dysfunction."

Journal • Retrospective data • Review • Dyslipidemia • Fibrosis • Hepatology • Hypertriglyceridemia • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease

Oxidative Stress Triggers Porcine Ovarian Granulosa Cell Apoptosis Through MAPK Signaling. (PubMed, Antioxidants (Basel)) - "Additionally, selonsertib pretreatment attenuated apoptosis in GCs by inhibiting H2O2-induced oxidative stress. In summary, our findings reveal that oxidative stress induced granulosa cell apoptosis via the MAPK signaling pathway, impairing proper follicular development in pigs."

Journal • Preclinical

Important negative trials in pulmonary hypertension. (PubMed, Curr Opin Pulm Med) - "This article provides an overview of the key learning points from these studies and reinforces the importance of the publication of all trials, irrespective of outcome, so that we can learn from negative studies and prioritize promising therapies and treatment pathways."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

ASK1 Inhibition Attenuates Elastase-Induced Pulmonary Emphysema (ATS 2025) - "Additionally, selonsertib decreased the expression of pro-inflammatory cytokines and reactive oxygen species, indicating a modulation of the inflammatory response and a positive effect on redox balance. Therefore, ASK1 inhibition may represent a promising therapeutic approach for COPD."

Alpha-1 Antitrypsin Deficiency • Chronic Obstructive Pulmonary Disease • Genetic Disorders • Hepatology • Immunology • Inflammation • Pulmonary Disease • Pulmonary Emphysema • Respiratory Diseases • ELANE

Plasma proteome signatures of ASK1 inhibition by selonsertib associate with efficacy in the MOSAIC randomized trial for diabetic kidney disease. (PubMed, BMC Nephrol) - "We further demonstrate that the effects of selonsertib on the plasma proteome are most pronounced in a subset of patients with poor baseline kidney function but who respond well to selonsertib treatment. This observation has implications for the future development of ASK1 inhibitors in a distinct patient population with DKD."

Clinical • Journal • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • MAP3K5

HPV16 E7 inhibits HBD2 expression by down-regulation of ASK1-p38 MAPK pathway in cervical cancer. (PubMed, Virol J) - "Our results implied that HPV16 E7 suppresses HBD2 expression via the inhibition of the ASK1-p38 MAPK signaling pathway, and this mechanism might be a key way of anti-tumor effect of Anisomycin. This study provided a novel insight into the expression and regulation mechanism of HBD2 in tumors and offered a possible therapeutic strategy by using defensins for cervical cancer in future."

Journal • Cervical Cancer • Oncology • Solid Tumor

ASK1 inhibition by selonsertib attenuates elastase-induced emphysema in mice. (PubMed, Life Sci) - "Moreover, higher doses of selonsertib were effective in reducing inflammatory cytokines (CX3CL1, IL-6, CCL2, and IL-1β), reactive oxygen species, and apoptosis. These findings suggest that ASK1 plays a critical role in the development of elastase-induced emphysema in mice and could be a target for COPD treatment."

Journal • Preclinical • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Pulmonary Emphysema • Respiratory Diseases • CCL2 • CX3CL1 • ELANE • IL1B • IL6

ASK1 limits kidney glucose reabsorption, growth, and mid-late proximal tubule KIM-1 induction when diabetes and Western diet are combined with SGLT2 inhibition. (PubMed, Am J Physiol Renal Physiol) - "This study explored individual and combined kidney effects of selonsertib and the anti-hyperglycemic SGLT2 inhibitor (SGLT2i) dapagliflozin in Western diet-fed male Akita mice, a murine model of early type 1 diabetes mellitus showing signs of systemic but no kidney inflammation. Combined ASK1i+SGLT2i increased tubular injury score but not signs of kidney inflammation or fibrosis beyond a robust increase in kidney mRNA expression of Il6, Ccl2 (Mcp1) and Timp1, associated with increased plasma IL-6 levels. The data support the hypothesis that house-keeping functions of ASK1 limit glucose reabsorption and the associated growth and cellular stress induced in mid to late proximal tubule by combining hyperglycemia and Western diet with SGLT2 inhibition."

Journal • Acute Kidney Injury • Diabetes • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus • CCL2 • CXCL1 • CXCL10 • IL6 • KIM1 • TIMP1

Comparison of Pharmacological Therapies for Metabolic Dysfunction-Associated Steatohepatitis: Systematic Review and Network Meta-analysis (APASL 2025) - "For the co-primary endpoint of fibrosis improvement without MASH resolution, pegozafermin, cilofexor + firsocostat, survodutide, obeticholic acid, tirzepatide, and resmetirom were significantly better than placebo in improving ≥ 1 fibrosis stage without worsening MASH. Pegozafermin (SUCRA: 90.18), cilofexor plus firsocostat (SUCRA: 82.82), and cilofexor plus selonsertib (SUCRA: 79.62) were ranked the most effective interventions. For the co-primary endpoint of MASH resolution without worsening fibrosis, pegozafermin, survodutide, tirzepatide, efruxifermin, liraglutide, vitamin E + pioglitazone, resmetirom, semaglutide, pioglitazone, and lanifibranor were significantly better than placebo... This study provides updated rank-order efficacy of MASH pharmacological therapies for fibrosis regression and MASH resolution. These data are helpful to inform practice and clinical trial design."

Retrospective data • Review • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

A positive feedback loop of OTUD1 and c-Jun driven by leptin expedites stemness maintenance in ovarian cancer. (PubMed, Oncogene) - "Notably, the disruption of the positive feedback loop by targeting c-Jun or ASK1/JNK with T-5224, selonsertib, or ibrutinib markedly inhibited the leptin-induced stemness maintenance of OCSCs and tumorigenicity. Our findings reveal a crucial mechanism for leptin-mediated stemness maintenance and indicate that targeting c-Jun or the identified positive feedback loop has translational potential for ovarian cancer patients."

Journal • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • JUN • LEP • OTUD1

Discovery of Novel Pyridin-2-yl Urea Inhibitors Targeting ASK1 Kinase and Its Binding Mode by Absolute Protein-Ligand Binding Free Energy Calculations. (PubMed, Int J Mol Sci) - "The inhibition (IC50) of compound 2 was 1.55 ± 0.27 nM, which was comparable to the known clinical inhibitor, Selonsertib...Absolute binding free energy (BFE) calculations based on molecular dynamics simulations further discriminated the binding modes, presenting good tendency with bioassay results. This strategy, underpinned by BFE calculations, has the great potential to expedite the drug discovery process in the targeting of ASK1 kinase."

Journal

Comparison of pharmacological therapies in metabolic dysfunction-associated steatohepatitis for fibrosis regression and MASH resolution: Systematic review and network meta-analysis. (PubMed, Hepatology) - "This study provides updated rank-order efficacy of MASH pharmacological therapies for fibrosis regression and MASH resolution. These data are helpful to inform practice and clinical trial design."

Journal • Retrospective data • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis