Redox Modulation in Hepatic Fibrosis - Translating NOX1/4 Inhibition to Therapy

Sep 30, 2026

Chronic liver disease (CLD) spans progressive disorders, including metabolic dysfunction steatotic-associated liver disease (MASLD) and primary biliary cholangitis (PBC), creating a major global health burden with limited effective treatments. Fibrogenesis results from intertwined cellular stress, inflammation, and wound-healing responses, where NOX1 and NOX4 drive hepatic oxidative stress, fibrogenic signaling, and inflammation. Setanaxib, an oral dual inhibitor of NOX1/4, is reviewed across molecular pharmacology, translational models, and clinical evidence, showing pleiotropic antifibrotic effects and supportive safety data, including improvements in fatigue and quality of life. The paper also analyzes paradoxical NOX4 roles and compares future redox-targeted hepatoprotective strategies, including AI-driven predictive modeling for patient stratification.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Abstract

1. Introduction

2. The NOX1/NOX4 Axis: Distinct Mechanisms in Hepatic Signaling and Fibrosis

Review Redox Modulation in Hepatic Fibrosis: Translating NOX1/4 Inhibition to Therapy Ghaith K. Mansour 1, Ahmad W. Hajjar 2, Irene Marafini 3,4 and Giovanni Monteleone 3,4, * Academic Editor: Clare Selden Received: 12 November 2025 Revised: 9 December 2025 Accepted: 17 December 2025 Published: 23 December 2025 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 College of Pharmacy, Alfaisal University, Riyadh P.O. Box 50927, Saudi Arabia; [gkmansour@alfaisal.edu](gkmansour@alfaisal.edu) 2 College of Medicine, Alfaisal University, Riyadh P.O. Box 50927, Saudi Arabia; [awhajjar@alfaisal.edu](awhajjar@alfaisal.edu) 3 Gastroenterology Unit, Azienda Ospedaliera Policlinico Tor Vergata, 00133 Rome, Italy; [marafini@med.uniroma2.it](marafini@med.uniroma2.it) 4 Department of Systems Medicine, University of “Tor Vergata”, 00133 Rome, Italy * Correspondence: [gi.monteleone@med.uniroma2.it](gi.monteleone@med.uniroma2.it); Tel.: +39-06-20903702; Fax: +39-06-72596391 Abstract Chronic liver disease (CLD) encompasses a spectrum of progressive disorders, including metabolic dysfunction steatotic-associated liver disease (MASLD) and primary biliary cholangitis (PBC), which together represent a significant global health burden with few effective therapeutic options. The fibrogenic process, common to most forms of CLD, is driven by a complex interplay of cellular stress, inflammation, and wound-healing responses. Nicotinamide adenine dinucleotide phosphate oxidase isoforms 1 and 4 (NOX1 and NOX4) have emerged as key enzymatic sources of reactive oxygen species (ROS), serving as central mediators of hepatic oxidative stress, fibrogenesis, and inflammation. Setanaxib is a first-in-class, orally bioavailable, selective dual inhibitor of NOX1 and NOX4 that has progressed to clinical evaluation. This review synthesizes current knowledge on the molecular pharmacology of the NOX1/4 axis, preclinical evidence from translational models, and clinical trial outcomes to critically assess the therapeutic potential of targeted NOX inhibition in hepatic fibrosis. By attenuating hepatic stellate cell activation, modulating TGF-β signaling, reducing extracellular matrix (ECM) deposition, and regulating hepatic macrophage polarization, setanaxib exhibits pleiotropic antifibrotic effects. 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. Keywords: NADPH oxidase 1 (NOX4); reactive oxygen species (ROS); metabolic dysfunction steatotic-associated liver disease; primary biliary cholangitis 1. Introduction Chronic liver disease (CLD) remains a major global health burden, affecting over one-quarter of the world’s population and contributing substantially to morbidity and mortality [1] . Among the spectrum of CLD, metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a leading cause. Regardless of etiology, hepatic fibrosis is the shared pathological outcome, resulting from sustained injury and dysregulated woundhealing processes. The excessive deposition of extracellular matrix (ECM) disrupts liver architecture, progressing to cirrhosis, liver failure, or hepatocellular carcinoma (HCC) [2] . Reactive oxygen species (ROS) are central mediators of fibrogenic signaling. While ROS can origi

FAQs

What roles do NOX1 and NOX4 play in hepatic oxidative stress and fibrosis?

NOX1 and NOX4 are key enzymatic sources of reactive oxygen species (ROS), mediating hepatic oxidative stress, fibrogenesis, and inflammation. Their downstream effects include stellate cell activation and extracellular matrix remodeling.

What is setanaxib and why is it considered a therapeutic candidate for hepatic fibrosis?

Setanaxib is an orally bioavailable, selective dual inhibitor of NOX1 and NOX4. It is reported to attenuate hepatic stellate cell activation, modulate TGF-β signaling, reduce extracellular matrix deposition, and influence macrophage polarization.

How does the review describe the translational evidence for targeting the NOX1/4 axis?

The review synthesizes molecular pharmacology of the NOX1/4 axis, preclinical data from translational models, and clinical trial outcomes. It uses this evidence to evaluate the therapeutic potential of targeted NOX inhibition in hepatic fibrosis.

Sep 30, 2026

Uploaded by Sophia Brooks