selonsertib (GS-4997) / Gilead - LARVOL DELTA

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

GS-4997 halts the progression of tubulointerstitial injury in lupus nephritis. (PubMed, FASEB J) - "Pharmacological inhibition of ASK1 may prevent the progression of tubulointerstitial injury via inhibiting the ASK1/MAPK pathway in LN. Therefore, our findings demonstrate the potential use of GS-4997 for LN treatment."

Journal • Fibrosis • Glomerulonephritis • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease

Synthesis and biological evaluation of quinoxaline derivatives as ASK1 inhibitors. (PubMed, J Enzyme Inhib Med Chem) - "Its cell survival rate was significantly higher than GS-4997, indicating its good safety in normal human liver LO2 cells...Further biochemical analyses revealed that 26e could reduce the content of T-CHO, LDL, and TG in FFA-induced LO2 cells, and had the potential to treat non-alcoholic fatty disease. These findings provide a good choice for the future development of ASK1 inhibitors."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Multiple Sclerosis

Cardiac tumour necrosis factor receptor-associated factor 7 mediates the ubiquitination of apoptosis signal-regulating kinase 1 and aggravates cardiac hypertrophy. (PubMed, Cardiovasc Res) - "In summary, we identified TRAF7 as an essential regulator during cardiac hypertrophy, and modulation of the regulatory axis between TRAF7 and ASK1 could be a novel therapeutic strategy to prevent this pathological process."

Journal • Cardiovascular • Oncology • Targeted Protein Degradation

Umbelliprenin improved anti-proliferative effects of ionizing radiation on adult T-cell leukemia/lymphoma cells via interaction with CDK6; an in vitro and in silico study. (PubMed, Int J Immunopathol Pharmacol) - "Molecular docking revealed a favorable binding interaction between UMB and the ATP-binding site of CDK6, with a JAMDA score of -2.131, surpassing the control selonsertib. The current study provides evidence that UMB enhances the anti-proliferative effects of IR on ATL cells, and highlights the significance of targeting CDK6 in combinatorial approaches."

Journal • Preclinical • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA5 • CD44 • CDK6 • CFLAR • MYC

Selonsertib in Patients with Diabetic Kidney Disease: A Phase 2b Randomized Active Run-In Clinical Trial. (PubMed, J Am Soc Nephrol) - "Selonsertib attenuated the decline in eGFRcr over up to 84 weeks; however, it resulted in a numerically higher number of patients reaching a kidney clinical event and a numerically higher rate of investigator-reported acute kidney injury."

Journal • P2b data • Acute Kidney Injury • CNS Disorders • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Immunological mechanisms in steatotic liver diseases: An overview and clinical perspectives. (PubMed, Clin Mol Hepatol) - "Immunological modulations targeting hepatocyte death, inflammatory reactions and gut microbiome include N-acetylcysteine, selonsertib, F-652, prednisone, pentoxifylline, anakinra, JKB-121, HA35, obeticholic acid, probiotics, prebiotics, antibiotics and FMT. Understanding the immunological mechanisms underlying in SLD is crucial for advancing clinical therapeutic strategies."

Journal • Fibrosis • Gastrointestinal Cancer • Hepatology • Immunology • Liver Cancer • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor • CD4

Targeting ASK1 by CS17919 alleviates kidney- and liver-related diseases in murine models. (PubMed, Animal Model Exp Med) - "CS17919 showed cell protective, anti-inflammatory, and antifibrotic effects in vitro and in vivo, suggesting its therapeutic potential for metabolic-related kidney and liver diseases."

Journal • Preclinical • Chronic Kidney Disease • Diabetic Nephropathy • Fibrosis • Glomerulonephritis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Nephrology • Renal Disease

Digital pathology with artificial intelligence analysis provides insight to the efficacy of anti-fibrotic compounds in human 3D MASH model (EASL-ILC 2024) - "In summary, the phenotypic quantification of fibrosis of MASH hLiMTs combined with secretion of pro-fibrotic biomarkers and transcriptomics represents a promising drug discovery tool for assessing anti-fibrotic compounds."

Clinical • Fibrosis • Hepatology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • TGFB1 • TIMP1

Artificial intelligence-derived granular histological markers of fibrosis from hematoxylin and eosin-stained whole slide images associate with non-invasive tests of fibrosis and prognosis to cirrhosis in patients with metabolic dysfunction-associated steatohepatitis (EASL-ILC 2024) - " We deployed NASH Explore on 4454 H&E WSIs from 3 clinical datasets (STELLAR 3 and STELLAR 4, trials of selonsertib on MASH patients with F3 or F4 fibrosis, respectively, and ATLAS, a trial testing combinations of selonsertib, cilofexor, and firsocosat in F4 MASH patients). Using NASH Explore HIFs, we showed that relative areas of pathological and nodular fibrosis positively associate with non-invasive measurement of fibrosis severity and prognosis. Further research is required to validate the association between NITs and granular histological features, which may support the assessment of MASH disease progression or regression through non-invasive surrogates of liver histopathology."

Clinical • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Artificial intelligence models deployed at scale on hematoxylin and eosin-stained whole slide images reveal stage-dependent collagen composition in metabolic dysfunction-associated steatohepatitis (EASL-ILC 2024) - " NASH Explore models were deployed on H&E-stained liver biopsies from the STELLAR-3 and STELLAR-4 trials of selonsertib, which enrolled MASH patients with bridging fibrosis or compensated cirrhosis, respectively... Characterization of pathological fibrosis and non-pathological collagen features via AI digital pathology yields an understanding of MASH fibrosis progression beyond the resolution provided by CRN scoring. The presence of expected associations, such as nodular fibrosis in F4, provides biological support for empirically-validated AI fibrosis staging. Quantifying fibrosis directly from scanned H&E images with NASH Explore requires no custom microscopy and is scalable for applications in drug development, enhancing understanding of therapeutic mechanisms for anti-fibrotic drugs, and potentially use in clinical care."

Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Paired assessment of enhanced liver fibrosis (ELF) and fibrosis-4 (FIB-4) scores is associated with an elevated risk of liver-related clinical events in participants with advanced fibrosis due to metabolic dysfunction-associated steatohepatitis (MASH) (EASL-ILC 2024) - P2, P2b, P3 | " Data from participants with advanced fibrosis due to MASH enrolled in four placebo- controlled trials evaluating simtuzumab (NCT02466516, NCT01672879) and selonsertib (NCT03053050, NCT03053063) were analyzed. In this cohort of participants with advanced fibrosis due to MASH, paired evaluation of ELF and FIB-4 demonstrated a significant association with liver-related clinical events. Further research is required to validate this model, which could serve to identify and enrich trials designed to test drugs that could prevent or attenuate MASH disease progression."

Clinical • Metastases • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Selonsertib, an ASK1 Inhibitor, Ameliorates Ovalbumin-Induced Allergic Asthma during Challenge and Sensitization Periods. (PubMed, Biomol Ther (Seoul)) - "Selonsertib also suppressed the IgE levels in serum and the protein levels of IL-13 in the bronchoalveolar lavage fluid. These results suggest that selonsertib may ameliorate allergic asthma by suppressing immune responses and be applicable to allergic asthma."

Journal • Allergy • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • IL13

Abrogating PDK4 activates autophagy-dependent ferroptosis in breast cancer via ASK1/JNK pathway. (PubMed, J Cancer Res Clin Oncol) - "To sum up, deficiency of PDK4 activated ASK1/JNK pathway to stimulate autophagy-dependent ferroptosis in breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • MAPK8 • PDK4