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Pre-clinical evidence of a dual NADPH oxidase 1/4 inhibitor (setanaxib) in liver,kidney and lung fibrosis |
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| Authors: | Victor J Thannickal Karin Jandeleit-Dahm Cédric Szyndralewiez Natalie J Török |
| Institution: | 1. John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA;2. Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Contribution: Conceptualization (equal), Formal analysis (equal), Investigation (equal), Validation (equal), Visualization (equal), Writing - original draft (equal), Writing - review & editing (equal);3. Calliditas Therapeutics Suisse SA, Geneva, Switzerland Contribution: Conceptualization (equal), Formal analysis (equal), Investigation (equal), Methodology (lead), Validation (equal), Visualization (equal), Writing - original draft (equal), Writing - review & editing (equal);4. Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, California, USA Contribution: Conceptualization (equal), Formal analysis (equal), Investigation (equal), Validation (equal), Visualization (equal), Writing - original draft (equal), Writing - review & editing (equal) |
| Abstract: | Fibrosis describes a dysregulated tissue remodelling response to persistent cellular injury and is the final pathological consequence of many chronic diseases that affect the liver, kidney and lung. Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) enzymes produce reactive oxygen species (ROS) as their primary function. ROS derived from NOX1 and NOX4 are key mediators of liver, kidney and lung fibrosis. Setanaxib (GKT137831) is a first-in-class, dual inhibitor of NOX1/4 and is the first NOX inhibitor to progress to clinical trial investigation. The anti-fibrotic effects of setanaxib in liver, kidney and lung fibrosis are supported by multiple lines of pre-clinical evidence. However, despite advances in our understanding, the precise roles of NOX1/4 in fibrosis require further investigation. Additionally, there is a translational gap between the pre-clinical observations of setanaxib to date and the applicability of these to human patients within a clinical setting. This narrative review critically examines the role of NOX1/4 in liver, kidney and lung fibrosis, alongside the available evidence investigating setanaxib as a therapeutic agent in pre-clinical models of disease. We discuss the potential clinical translatability of this pre-clinical evidence, which provides rationale to explore NOX1/4 inhibition by setanaxib across various fibrotic pathologies in clinical trials involving human patients. |
| Keywords: | fibrosis kidney diseases liver cirrhosis liver diseases NADPH oxidases pulmonary fibrosis reactive oxygen species setanaxib |