Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1785097312106708992 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10459039 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT mohammedosamaa sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT abdelreheimmustafaahmed sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT alamrimohannadmohammads sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT alfaifijaber sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT adammasoudie sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT salehlobnaa sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT farragalshaimaaa sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT yahiaamaribrahimomer sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT abdelghanysameh sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT alqahtaniabdulelahaljarallah sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT bahashwanemad sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT eltahirhananb sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT mohammednahida sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT elwakeelhends sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT hazemsarah sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations AT sabersameh sta9090asapotentialtherapeuticagentforliverfibrosisbymodulatingthehsp90tbriiproteasomeinterplaynovelinsightsfrominvitroandinvivoinvestigations |