Cell-Permeable PROTAC Degraders against KEAP1 Efficiently Suppress Hepatic Stellate Cell Activation through the Antioxidant and Anti-Inflammatory Pathway

Fengqin Wang, Ying Zhan, Manman Li, Lidan Wang, Austin Zheng, Changbai Liu, Hu Wang, Tao Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Accumulating evidence indicates that oxidative stress and inflammation are involved in the physiopathology of liver fibrogenesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor, which regulates the expression of redox regulators to establish cellular redox homeostasis. The Nrf2 modulator can serve as a primary cellular defense against the cytotoxic effects of oxidative stress. We designed a chimeric Keap1-Keap1 peptide (KKP1) based on the proteolysis-targeting chimera technology. The KKP1 peptide not only can efficiently penetrate into the rat hepatic stellate cell line (HSC-T6) cells but also can induce Keap1 protein degradation by the ubiquitination-proteasome degradation pathway, which releases Nrf2 and promotes the transcriptional activity of the Nrf2/antioxidant response element pathway. It then activates the protein expression of the downstream antioxidant factors, the glutamate-cysteine ligase catalytic subunit and heme oxygenase-1 (HO-1). Finally, Keap1 protein degradation inhibits the nuclear factor-kappaB inflammatory signal pathway, the downstream inflammatory factor tumor necrosis factor alpha, and the interleukin-1beta protein expression and further inhibits the expression of the fibrosis biomarker gene. The current research suggests that our designed KKP1 may provide a new avenue for the future treatment of liver fibrosis.

Original languageEnglish (US)
Pages (from-to)76-87
Number of pages12
JournalACS Pharmacology and Translational Science
Volume6
Issue number1
DOIs
StatePublished - Jan 13 2023

Keywords

  • Keap1
  • Nrf2
  • PROTAC
  • cell penetrating peptide
  • fibrosis
  • hepatic stellate cells

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

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