From liver fibrosis to hepatocarcinogenesis: Role of excessive liver H <sub>2</sub>O <sub>2</sub> and targeting nanotherapeutics

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Abstract

Liver fibrosis and hepatocellular carcinoma (HCC) have been worldwide threats nowadays. Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage. In pathological liver, excessive H ₂O ₂ is generated and accumulated, which impacts the functionality of hepatocytes, Kupffer cells (KCs) and hepatic stellate cells (HSCs), leading to genesis of fibrosis and HCC. H ₂O ₂ accumulation is associated with overproduction of superoxide anion (O ₂ ^•−) and abolished antioxidant enzyme systems. Plenty of therapeutics focused on H ₂O ₂ have shown satisfactory effects against liver fibrosis or HCC in different ways. This review summarized the reasons of liver H ₂O ₂ accumulation, and the role of H ₂O ₂ in genesis of liver fibrosis and HCC. Additionally, nanotherapeutics targeting H ₂O ₂ were summarized for further consideration of antifibrotic or antitumor therapy.

Graphical abstract

Highlights

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Liver fibrosis and HCC are closely related because ROS induced liver damage and inflammation, especially over-cumulated H ₂O ₂.
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Excess H ₂O ₂ diffusion in pathological liver was due to increased metabolic rate and diminished cellular antioxidant systems.
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Freely diffused H ₂O ₂ damaged liver-specific cells, thereby leading to fibrogenesis and hepatocarcinogenesis.
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Nanotherapeutics targeting H ₂O ₂ are summarized for treatment of liver fibrosis and HCC, and also challenges are proposed.

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Hepatocellular carcinoma

Josep Llovet, Robin Kate Kelley, Augusto Villanueva … (2021)

Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West. Moreover, non-alcoholic steatohepatitis-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and three additional therapies have obtained accelerated FDA approval owing to evidence of efficacy. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies, or even combinations of two immunotherapy regimens. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages.

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Ferroptosis: past, present and future

Jie Li, Feng Cao, He-liang Yin … (2020)

Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases.

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Karen Bedard, Karl-Heinz Krause (2007)

For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91(phox)), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). Activation mechanisms and tissue distribution of the different members of the family are markedly different. The physiological functions of NOX family enzymes include host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. NOX enzymes also contribute to a wide range of pathological processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased NOX activity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration. This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.

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Author and article information

Contributors

Mengyun Peng

Gang Cao

Journal

Journal ID (nlm-ta): Bioact Mater

Journal ID (iso-abbrev): Bioact Mater

Title: Bioactive Materials

Publisher: KeAi Publishing

ISSN (Electronic): 2452-199X

Publication date PMC-release: 12 November 2022

Publication date Collection: May 2023

Publication date (Electronic): 12 November 2022

Volume: 23

Pages: 187-205

Affiliations

[1]School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310000, PR China

Author notes

[∗ ]Corresponding author. pmy@ 123456zcmu.edu.cn

[∗∗ ]Corresponding author. caogang33@ 123456163.com

[1]

These authors contributed equally to this work.

Article

Publisher Item ID: S2452-199X(22)00465-0

DOI: 10.1016/j.bioactmat.2022.11.001

PMC ID: 9663332

PubMed ID: 36406254

SO-VID: 0844d643-5f5c-473f-ac41-5a2490065cd9

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 4 September 2022

Date revision received : 23 October 2022

Date accepted : 6 November 2022

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