Cell-Permeable PROTAC Degraders against KEAP1 Efficiently Suppress Hepatic Stellate Cell Activation through the Antioxidant and Anti-Inflammatory Pathway.
Fengqin WangYing ZhanManman LiLidan WangAustin ZhengChangbai LiuHu WangTao WangPublished in: ACS pharmacology & translational science (2022)
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.
Keyphrases
- oxidative stress
- nuclear factor
- protein protein
- transcription factor
- toll like receptor
- diabetic rats
- liver fibrosis
- dna damage
- ischemia reperfusion injury
- induced apoptosis
- cell therapy
- anti inflammatory
- poor prognosis
- small molecule
- binding protein
- single cell
- heat shock
- gene expression
- long non coding rna
- mesenchymal stem cells
- stem cells
- dna methylation
- genome wide
- inflammatory response
- signaling pathway
- cancer therapy
- drug delivery
- copy number
- heat stress
- cell proliferation
- heat shock protein
- innate immune
- genome wide identification
- electron transfer
- replacement therapy