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Targeting Oxidative Stress for the Treatment of Liver Fibrosis

  • Theerut Luangmonkong
  • Su Suriguga
  • Henricus A. M. Mutsaers
  • Geny M. M. Groothuis
  • Peter Olinga
  • Miriam Boersema
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series


Oxidative stress is a reflection of the imbalance between the production of reactive oxygen species (ROS) and the scavenging capacity of the antioxidant system. Excessive ROS, generated from various endogenous oxidative biochemical enzymes, interferes with the normal function of liver-specific cells and presumably plays a role in the pathogenesis of liver fibrosis. Once exposed to harmful stimuli, Kupffer cells (KC) are the main effectors responsible for the generation of ROS, which consequently affect hepatic stellate cells (HSC) and hepatocytes. ROS-activated HSC undergo a phenotypic switch and deposit an excessive amount of extracellular matrix that alters the normal liver architecture and negatively affects liver function. Additionally, ROS stimulate necrosis and apoptosis of hepatocytes, which causes liver injury and leads to the progression of end-stage liver disease. In this review, we overview the role of ROS in liver fibrosis and discuss the promising therapeutic interventions related to oxidative stress. Most importantly, novel drugs that directly target the molecular pathways responsible for ROS generation, namely, mitochondrial dysfunction inhibitors, endoplasmic reticulum stress inhibitors, NADPH oxidase (NOX) inhibitors, and Toll-like receptor (TLR)-affecting agents, are reviewed in detail. In addition, challenges for targeting oxidative stress in the management of liver fibrosis are discussed.


Liver fibrosis Oxidative stress Reactive oxygen species Therapeutic target 



Adenosine diphosphate


Alcoholic liver disease


Alanine transaminase


Bile duct-ligated




Carbon tetrachloride


Coenzyme A


Coenzyme Q10


Cytochrome P450


Cytochrome C


Docosahexaenoic acid


Extracellular matrix


Eukaryotic translation initiation factor 2 alpha


Eicosapentaenoic acid


Endoplasmic reticulum


Endoplasmic reticulum oxidoreductin 1 alpha


Flavin adenine dinucleotide




Hydrogen peroxide


Hepatitis B virus


Hepatitis C virus


High-mobility group box




Hydroxyl radical


Hepatic stellate cells


Interleukin-1 receptor-associated kinase-1


Kupffer cells


Low-density lipoprotein receptor






Nicotinamide adenine dinucleotide


Nonalcoholic fatty liver disease


Nonalcoholic steatohepatitis


Nuclear factor (erythroid-derived 2)-like 2


Nuclear factor kappa-light-chain-enhancer of activated B cells


Nucleotide-binding domain, leucine-rich repeat family, pyrin domain-containing 3


NADPH oxidase




Superoxide anion


Platelet-derived growth factor


Protein disulfide isomerase


Protein kinase R (PKR)-like endoplasmic reticulum kinase


Reactive oxygen species


Transforming growth factor beta


Toll-like receptor


Tumor necrosis factor alpha


Unfolded protein response


Conflict of Interest

No conflict of interest.

Financial Support

This work was supported by ZonMw (grant number: 114021010), China Scholarship Council, and Lundbeckfonden (grant number: R231-2016-2344).

Author’s Contributions

T. Luangmonkong and S. Suriguga, searching, analyzing, and selecting publications and drafting and editing of the manuscript; H. A. M. Mutsaers and G. Groothuis, revising of the manuscript for important intellectual content; P. Olinga, supervising the scope of the manuscript and revising the manuscript for important intellectual content; M. Boersema, reviewing the drafted manuscript and contributing important intellectual content to the final manuscript.


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Theerut Luangmonkong
    • 1
    • 2
  • Su Suriguga
    • 1
  • Henricus A. M. Mutsaers
    • 1
    • 3
  • Geny M. M. Groothuis
    • 4
  • Peter Olinga
    • 1
  • Miriam Boersema
    • 1
  1. 1.Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenThe Netherlands
  2. 2.Department of Pharmacology, Faculty of PharmacyMahidol UniversityBangkokThailand
  3. 3.Department of Clinical MedicineAarhus UniversityAarhusDenmark
  4. 4.Department of Pharmacokinetics, Toxicology and TargetingUniversity of GroningenGroningenThe Netherlands

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