The final, formatted version of the article will be published soon.
ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Gastrointestinal and Hepatic Pharmacology
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1454829
This article is part of the Research Topic New Targets and Strategies for the Prevention and Treatment of Organ Fibrosis, Volume III View all 3 articles
STA-9090 in Combination with a Statin Exerts Enhanced Protective Effects in Rats Fed a High-Fat Diet and Exposed to Diethylnitrosamine and Thioacetamide
Provisionally accepted- 1 Delta University for Science and Technology, Al Mansurah, Egypt
- 2 King Faisal University, Al-Ahsa, Eastern Province, Saudi Arabia
- 3 Shaqra University, Shaqraa, Riyadh, Saudi Arabia
- 4 Qassim University, Buraidah, Al-Qassim, Saudi Arabia
- 5 Taif University, Ta'if, Saudi Arabia
Liver fibrosis is a significant global health burden that lacks effective therapies. It can progress to cirrhosis and hepatocellular carcinoma (HCC). Aberrant hedgehog pathway activation is a key driver of fibrogenesis and cancer, making hedgehog inhibitors potential antifibrotic and anticancer agents. We evaluated simvastatin and STA-9090, alone and combined, in rats fed a high-fat diet (HFD) and exposed to diethylnitrosamine and thioacetamide (DENA/TAA).Simvastatin inhibits HMG-CoA reductase, depleting cellular cholesterol required for Sonic hedgehog (Shh) modification and signaling. STA-9090 directly inhibits HSP90 chaperone interactions essential for Shh function. We hypothesized combining these drugs may provide liver protective effects through complementary targeting of the hedgehog pathway. Endpoints assessed included liver function tests, oxidative stress markers, histopathology, extracellular matrix proteins, inflammatory cytokines, and hedgehog signaling components. HFD and DENA/TAA caused aberrant hedgehog activation, contributing to fibrotic alterations with elevated liver enzymes, oxidative stress, dyslipidemia, inflammation, and collagen deposition.Monotherapies with simvastatin or STA-9090 improved these parameters, while the combination treatment provided further enhancements, including improved survival, nearnormal liver histology, and compelling hedgehog pathway suppression. Our findings demonstrate the enhanced protective potential of combined HMG CoA reductase and HSP90 inhibition in rats fed a HFD and exposed to DENA and TAA. This preclinical study could help translate hedgehog-targeted therapies to clinical evaluation for treating this major unmet need.
Keywords: STA-9090, Hsp90, HMG-CoA reductase, Hedgehog pathway, Inflammation/Fibrosis, Dyslipideamia
Received: 25 Jun 2024; Accepted: 26 Aug 2024.
Copyright: © 2024 Abdelhamid, Saber, Hamad, Abdel-reheim, Ellethy, Amer, Abdel-Hamed, Mohamed, Ahmed, Elsisi, Khodeir, Alkhamiss, A., Abu Elgasim, Almansour, Elesawy and Elmorsy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Sameh Saber, Delta University for Science and Technology, Al Mansurah, Egypt
Rabab S. Hamad, King Faisal University, Al-Ahsa, 31982, Eastern Province, Saudi Arabia
Mustafa A. Abdel-reheim, Shaqra University, Shaqraa, Riyadh, Saudi Arabia
Elsayed A. Elmorsy, Qassim University, Buraidah, 52571, Al-Qassim, Saudi Arabia
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.