Table 1 NRF2 function in hepatitis virus

HCV

During the early stages of HCV protein production in Huh7 cells, researchers have pinpointed the molecular mechanisms by which specific HCV proteins regulate the Nrf2/ARE pathway. These molecular processes may have a role in the acute phase of the illness when viral multiplication impacts the antioxidant defense system.

In addition to inducing high ROS levels, the core, E1, E2, NS4B, and NS5A proteins of HCV may also activate the Nrf2/ARE pathway. Multiple protein kinases are involved in the activation, which is only partly ROS-dependent.

Taking antioxidants during acute hepatitis C infection may not be the best idea. Patients should be treated with antioxidants to prevent the long-term consequences of stress because of the possibility that the Nrf2/ARE pathway will be inactivated during the chronic stage.

In vitro (HUH7 Cells)

[86]

HCV

Scientists want to learn more about how HCV’s atypical mechanism leading to an impeded Nrf2/ARE-signaling in HCV-replicating cells affects the activation of autophagy. Autophagy, viral particle release, increased ROS levels, pS349 p62 production, and reduced Nrf2/ARE-signaling are all interconnected processes that will be better understood.

HCV counteracts pS349 p62-induced activation of Nrf2 by suppressing Nrf2/ARE-mediated gene expression. This keeps ROS levels high, which triggers autophagy and promotes HCV particle release.

This makes the viral life cycle and virus-associated pathophysiology a potential target for restoring Nrf2/ARE signaling, which results in ROS detoxification.

In vitro (Huh7-derived cell line Huh7.5)

[87]

HBV

Studying the physiological importance of the viral life cycle and pathogenesis, researchers assess HBV’s ability to control the expression of ARE-regulated genes, uncover the processes by which HBV interferes, and more.

HBV-positive cells are better protected from oxidative damage because of the Nrf2/ARE-mediated activation of cytoprotective genes. In addition, the expression of the Nrf2/ARE-regulated proteasomal component PSMB5 is markedly upregulated in HBV-positive cells, whereas the expression of PSMB5i downregulated significantly.

The immune system and endoplasmic reticulum overload do not cause as much oxidative damage to HBV-positive cells. Keeping the Nrf2/ARE system functional is crucial for host tissue survival during liver regeneration. Increased constitutive proteasome activity guarantees that unfolded proteins are removed quickly and effectively. Reduced antigen processing occurs due to impaired immunoproteasome activity.

In vitro (HepG2, Huh7.5, and the HBV-positive stable cell lines HepG2.2.15 and HepAD38)

[84]

HBV

Scientists explain how HBV/G-infected cells cannot secrete HBsAg and identify elements that contribute to the pathogenesis of the virus.

An increased number of ROIs is caused by intracellular HBsAg buildup and poor Nrf2 cytoprotective transcription factor activation. The ability to inactivate ROIs declines along with a reduction in HBV-induced Nrf2 activation.

The reduced ability of HBV/G-expressing cells to inactivate ROIs is consistent with the reduced induction of Nrf2-dependent genes, which results in a reduced induction of cytoprotective mechanisms. This may have implications for understanding the pathogenesis of viruses.

In vitro (HuH7.5 and HepG2)

[90]

HBV

This research aimed to characterize mechanisms leading to HBV/ G-associated pathogenesis by contrasting the morphogenesis and release of HBV-derived particles between HBV genotypes G and A2.

Genotype G’s aggregating PreS1PreS2 domain prevents ER access for HBsAg secretion and reduces the transcriptional activator activity of LHBs. Increased levels of ROIs are caused by the intracellular buildup of HBsAg and the failure to induce the cytoprotective transcription factor Nrf2. As a result, Ser-phosphorylation of IRS-1 occurs, which is known to disrupt insulin signaling and impede liver regeneration.

HBV/G infection, on the other hand, inhibits the Nrf2 pathway because of the accumulation of subviral HBsAg particles within the cell, and the expression of Nrf2 target genes is reduced in HBV/G replicating cells. In conclusion, Keap1/Nrf2 signaling is modulated in various ways by HBV genotype-specific regulatory proteins, which in turn uniquely affects the virus’s pathogenicity.

In vitro (HuH7.5 and HepG2)

[20, 90]

HDV

The purpose of this investigation was to examine how HDV antigens affect ROS generation and the expression of several ROS-generating enzymes, all of which have been reported in the context of other hepatitis viruses. Second, researchers wanted to see whether we could find evidence of a problem with the antioxidant defense Nrf2/ARE pathway. The third objective was to research how HDV antigens affect ER stress and the subsequent UPR. In this study, the authors demonstrated that L-HDAg, in conjunction with S-HDAg, promotes the ROS-producing enzymes NOX1, NOX4, CYP2E1, and Ero1, activates the Nrf2/ARE defensive pathway and triggers the UPR.

The Nrf2/ARE pathway, which regulates the expression of various AOEs, was activated by both HDV antigens. Finally, ER stress and the associated UPR were also triggered by HDV and its prominent antigen.

As a result, HDV may exacerbate the oxidative and ER stress brought on by HBV, increasing the diseases connected to HBV, such as inflammation, liver fibrosis, and the development of cirrhosis and HCC.

Overexpression of a series of ROS-generating extramitochondrial enzymes, activation of the Nrf2/ARE pathway that controls the expression of antioxidant enzymes, and induction of ER stress and a concomitant unfolded protein response are all triggered by HDV replication in liver cell lines and the simultaneous expression of the viral antigen(s). The importance of these occurrences in HDV pathogenesis may be shown in future research.

In vitro (Huh7 cells)

[91]