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Daclatasvir and Sofosbuvir Mitigate Hepatic Fibrosis Through Downregulation of TNF-α / NF-κB Signaling Pathway

Sherin Zakaria1, Alaa E El-Sisi2

  • 1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kaferelsheikh University, Kaferelsheikh, Egypt.

Current Molecular Pharmacology
|January 18, 2020
PubMed
Abstract

Insights

Sofosbuvir (SOF) and daclatasvir (DAC) show antifibrotic effects in liver fibrosis models, independent of their antiviral action. These drugs reduce fibrotic markers by downregulating TNF-α/NF-κB signaling and increasing Bcl-2 expression.

Area of Science:

  • Hepatology
  • Pharmacology
  • Molecular Biology

Background:

  • Hepatic fibrosis is a critical issue in chronic liver diseases like Hepatitis C Virus (HCV) infection.
  • Direct-acting antiviral (DAA) agents, including Sofosbuvir (SOF) and daclatasvir (DAC), are associated with reduced fibrotic markers in HCV patients.

Purpose of the Study:

  • To investigate whether the antifibrotic effects of SOF and DAC are dependent on their antiviral activity or directly induced by the drugs.
  • To elucidate the molecular mechanisms underlying the antifibrotic actions of SOF and DAC.

Main Methods:

  • Hepatic fibrosis was induced in rats using carbon tetrachloride (CCl4).
  • SOF and DAC were administered during the later stages of fibrosis induction.
  • Liver function, fibrotic markers (Hyaluronic acid, MMP-9), TNF-α/NF-κB pathway, and Bcl-2 expression were assessed.

Main Results:

  • SOF and DAC demonstrated significant antifibrotic effects, reducing hyaluronic acid and metalloproteinase-9 levels (P≤0.001).
  • Histopathological analysis revealed inhibited collagen deposition and activated hepatic stellate cell (HSC) suppression.
  • The antifibrotic action correlated with decreased TNF-α/NF-κB signaling and increased Bcl-2 expression.

Conclusions:

  • The antifibrotic effect of SOF and DAC is independent of their antiviral activity.
  • The antifibrotic mechanism involves downregulation of the TNF-α/NF-κB pathway and induction of Bcl-2.
Keywords:
Bcl-2NF-κBSofosbuvirTNF-αdaclatasvirhepatic fibrosis

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