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STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations

Liver fibrosis is a progressive condition characterized by the build-up of fibrous tissue resulting from long-term liver injury. Although there have been advancements in research and treatment, there is still a need for effective antifibrotic medication. HSP90 plays a crucial role in the development...

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Autores principales: Mohammed, Osama A., Abdel-Reheim, Mustafa Ahmed, Alamri, Mohannad Mohammad S., Alfaifi, Jaber, Adam, Masoud I. E., Saleh, Lobna A., Farrag, Alshaimaa A., Yahia, Amar Ibrahim Omer, Abdel-Ghany, Sameh, AlQahtani, AbdulElah Al Jarallah, Bahashwan, Emad, Eltahir, Hanan B., Mohammed, Nahid A., El-wakeel, Hend S., Hazem, Sara H., Saber, Sameh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10459039/
https://www.ncbi.nlm.nih.gov/pubmed/37630994
http://dx.doi.org/10.3390/ph16081080
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author Mohammed, Osama A.
Abdel-Reheim, Mustafa Ahmed
Alamri, Mohannad Mohammad S.
Alfaifi, Jaber
Adam, Masoud I. E.
Saleh, Lobna A.
Farrag, Alshaimaa A.
Yahia, Amar Ibrahim Omer
Abdel-Ghany, Sameh
AlQahtani, AbdulElah Al Jarallah
Bahashwan, Emad
Eltahir, Hanan B.
Mohammed, Nahid A.
El-wakeel, Hend S.
Hazem, Sara H.
Saber, Sameh
author_facet Mohammed, Osama A.
Abdel-Reheim, Mustafa Ahmed
Alamri, Mohannad Mohammad S.
Alfaifi, Jaber
Adam, Masoud I. E.
Saleh, Lobna A.
Farrag, Alshaimaa A.
Yahia, Amar Ibrahim Omer
Abdel-Ghany, Sameh
AlQahtani, AbdulElah Al Jarallah
Bahashwan, Emad
Eltahir, Hanan B.
Mohammed, Nahid A.
El-wakeel, Hend S.
Hazem, Sara H.
Saber, Sameh
author_sort Mohammed, Osama A.
collection PubMed
description Liver fibrosis is a progressive condition characterized by the build-up of fibrous tissue resulting from long-term liver injury. Although there have been advancements in research and treatment, there is still a need for effective antifibrotic medication. HSP90 plays a crucial role in the development of fibrosis. It acts as a molecular chaperone that assists in the proper folding and stability of TβRII, potentially regulating the signaling of TGF-β1. It has been established that TβRII can be degraded through the proteasome degradation system, either via ubiquitination-dependent or -independent pathways. In the present study, STA9090 demonstrated promising effects in both in vitro and in vivo models. It reduced LDH leakage, prolonged the survival rate of hepatocytes in rats with liver fibrosis, and improved liver function. Importantly, STA9090 exerted pleiotropic effects by targeting proteins involved in limiting collagen production, which resulted in improved microscopic features of the rat livers. Our findings suggest that STA9090-induced inhibition of HSP90 leads to the degradation of TβRII, a fibrogenic client protein of HSP90, through the activation of the 20S proteasomal degradation system. We also revealed that this degradation mechanism is not dependent on the autophagy–lysosomal pathway. Additionally, STA9090 was found to destabilize HIF-1α and facilitate its degradation, leading to the reduced transcription of VEGF. Moreover, STA9090’s ability to deactivate the NFκB signaling pathway highlights its potential as an anti-inflammatory and antifibrotic agent. However, further research is necessary to fully elucidate the underlying mechanisms and fully capitalize on the therapeutic benefits of targeting HSP90 and associated pathways.
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spelling pubmed-104590392023-08-27 STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations Mohammed, Osama A. Abdel-Reheim, Mustafa Ahmed Alamri, Mohannad Mohammad S. Alfaifi, Jaber Adam, Masoud I. E. Saleh, Lobna A. Farrag, Alshaimaa A. Yahia, Amar Ibrahim Omer Abdel-Ghany, Sameh AlQahtani, AbdulElah Al Jarallah Bahashwan, Emad Eltahir, Hanan B. Mohammed, Nahid A. El-wakeel, Hend S. Hazem, Sara H. Saber, Sameh Pharmaceuticals (Basel) Article Liver fibrosis is a progressive condition characterized by the build-up of fibrous tissue resulting from long-term liver injury. Although there have been advancements in research and treatment, there is still a need for effective antifibrotic medication. HSP90 plays a crucial role in the development of fibrosis. It acts as a molecular chaperone that assists in the proper folding and stability of TβRII, potentially regulating the signaling of TGF-β1. It has been established that TβRII can be degraded through the proteasome degradation system, either via ubiquitination-dependent or -independent pathways. In the present study, STA9090 demonstrated promising effects in both in vitro and in vivo models. It reduced LDH leakage, prolonged the survival rate of hepatocytes in rats with liver fibrosis, and improved liver function. Importantly, STA9090 exerted pleiotropic effects by targeting proteins involved in limiting collagen production, which resulted in improved microscopic features of the rat livers. Our findings suggest that STA9090-induced inhibition of HSP90 leads to the degradation of TβRII, a fibrogenic client protein of HSP90, through the activation of the 20S proteasomal degradation system. We also revealed that this degradation mechanism is not dependent on the autophagy–lysosomal pathway. Additionally, STA9090 was found to destabilize HIF-1α and facilitate its degradation, leading to the reduced transcription of VEGF. Moreover, STA9090’s ability to deactivate the NFκB signaling pathway highlights its potential as an anti-inflammatory and antifibrotic agent. However, further research is necessary to fully elucidate the underlying mechanisms and fully capitalize on the therapeutic benefits of targeting HSP90 and associated pathways. MDPI 2023-07-28 /pmc/articles/PMC10459039/ /pubmed/37630994 http://dx.doi.org/10.3390/ph16081080 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mohammed, Osama A.
Abdel-Reheim, Mustafa Ahmed
Alamri, Mohannad Mohammad S.
Alfaifi, Jaber
Adam, Masoud I. E.
Saleh, Lobna A.
Farrag, Alshaimaa A.
Yahia, Amar Ibrahim Omer
Abdel-Ghany, Sameh
AlQahtani, AbdulElah Al Jarallah
Bahashwan, Emad
Eltahir, Hanan B.
Mohammed, Nahid A.
El-wakeel, Hend S.
Hazem, Sara H.
Saber, Sameh
STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations
title STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations
title_full STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations
title_fullStr STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations
title_full_unstemmed STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations
title_short STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations
title_sort sta9090 as a potential therapeutic agent for liver fibrosis by modulating the hsp90/tβrii/proteasome interplay: novel insights from in vitro and in vivo investigations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10459039/
https://www.ncbi.nlm.nih.gov/pubmed/37630994
http://dx.doi.org/10.3390/ph16081080
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