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Evaluation of HZX-960, a novel DCN1-UBC12 interaction inhibitor, as a potential antifibrotic compound for liver fibrosis
- Source :
- Biochemistry and Cell Biology. July-August, 2022, Vol. 100 Issue 4, p309, 16 p.
- Publication Year :
- 2022
-
Abstract
- Liver fibrosis is a very common health problem and currently lacks effective treatments. Cullin RING E3 ligases (CRLs) regulate the turnover of ~20% of mammalian cell proteins. Neddylation, the process by which NEDD8 is covalently attached to cullin proteins through sequential enzymatic reactions, is critical for the activation of CRLs and was recently found to be elevated in liver fibrosis. NEDD8-activating enzyme El-specific inhibition led to the reduced liver damage characterized by decreased apoptosis, inflammation, and fibrosis. However, the relevance of a co-E3 ligase, DCN1, in liver fibrosis remains unclear. Here, a novel and potent DCN1-UBC12 interaction inhibitor HZX-960 was discovered with an [IC.sub.50] value of 9.37 nmol/L, which could inhibit the neddylation of cullin3. Importantly, we identified that HZX-960 treatment could attenuate transforming growth factor [beta]-induced liver fibrotic responses by reducing the deposition of collagen I and [alpha]-smooth muscle actin, and upregulating cellular NF-E2-related factor 2, hemeoxygenase 1, and NADPH quinone oxidoreductase-1 levels in two hepatic stellate cell lines. Additionally, DCN1 was shown to be unregulated in CCI4-induced mice liver tissue, and liver fibrotic signaling in mice was reduced by HZX-960. Therefore, our data demonstrated that HZX-960 possessed anti-liver fibrosis ability and that DCN1 may be a potential therapeutic target for liver fibrosis treatment. Keywords: DCN1, UBC12, interaction, NRF2, liver fibrosis La fibrose du foie constitue un probleme de sante tres repandu et il n'existe actuellement aucun traitement efficace. Les ligases E3 CRL (Cullin Ring E3 Ligases) regulent le renouvellement de ~20 % des proteines des cellules de mammiferes. La neddylation, le processus par lequel NEDD8 est attache de maniere covalente aux proteines cullines par des reactions enzymatiques sequentielles, est essentielle pour l'activation des CRL et il a ete recemment decouvert qu'elle etait elevee dans la fibrose du foie. L'inhibition specifique de l'enzyme activatrice de NEDD8 El, a conduit a la reduction des lesions hepatiques caracterisees par une diminution de l'apoptose, de l'inflammation et de la fibrose. Cependant, l'importance d'une ligase co-E3, DCN1, dans la fibrose hepatique reste floue. Les auteurs ont decouvert ici un nouvel inhibiteur puissant de l'interaction DCN1-UBC12, le HZX-960, dont la valeur de [CI.sub.50] est de 9,37 nmol/L et qui peut inhiber la neddylation de la culline3. Mais surtout, ils ont identifie que le traitement par le HZX-960 pouvait attenuer les reponses fibrotiques hepatiques induites par le TGF[beta] en reduisant le depot de collagene I et [alpha]-SMA, et en regulant a la hausse les niveaux cellulaires de NRF2, HO-1 et NQO1 dans deux lignees de cellules de Kupfer. De plus, il a ete demontre que DCN1 n'etait pas regule dans le tissu hepatique de souris expose au CCI4, et que la signalisation de la fibrose hepatique chez les souris etait reduite par le HZX-960. Par consequent, ces donnees ont demontre que le HZX-960 possede une capacite anti-fibrose hepatique, et que DCN1 peut etre une cible therapeutique potentielle pour le traitement de la fibrose hepatique. [Traduit par la Redaction] Mots-cles : DCN1, UBC12, interaction, NRF2, fibrose du foie<br />Introduction Liver fibrosis, as a regenerative process, was observed in various chronic liver injuries, including nonalcoholic fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and hepatitis B and C, which [...]
Details
- Language :
- English
- ISSN :
- 08298211
- Volume :
- 100
- Issue :
- 4
- Database :
- Gale General OneFile
- Journal :
- Biochemistry and Cell Biology
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.719647539
- Full Text :
- https://doi.org/10.1139/bcb-2021-0585