STA-9090 in combination with a statin exerts enhanced protective effects in rats fed a high-fat diet and exposed to diethylnitrosamine and thioacetamide

Amir Mohamed Abdelhamid; Sameh Saber; Rabab S Hamad; Mustafa Ahmed Abdel-Reheim; Abousree T Ellethy; Maha M Amer; Mohamed R Abdel-Hamed; Enas A Mohamed; Syed Suhail Ahmed; Hossam A Elsisi; Mostafa M Khodeir; Abdullah S Alkhamiss; AlSalloom A A; Mawahib Ahmed Elawad Abu Elgasim; Zainab H Almansour; Basem H Elesawy; Elsayed A Elmorsy

doi:10.3389/fphar.2024.1454829

STA-9090 in combination with a statin exerts enhanced protective effects in rats fed a high-fat diet and exposed to diethylnitrosamine and thioacetamide

Front Pharmacol. 2024 Sep 4:15:1454829. doi: 10.3389/fphar.2024.1454829. eCollection 2024.

Authors

Amir Mohamed Abdelhamid¹, Sameh Saber¹, Rabab S Hamad^{2

3}, Mustafa Ahmed Abdel-Reheim^{4

5}, Abousree T Ellethy⁶, Maha M Amer^{7

8}, Mohamed R Abdel-Hamed^{7

8}, Enas A Mohamed^{7

9}, Syed Suhail Ahmed¹⁰, Hossam A Elsisi^{11

12}, Mostafa M Khodeir^{13

14}, Abdullah S Alkhamiss¹³, AlSalloom A A¹³, Mawahib Ahmed Elawad Abu Elgasim¹⁵, Zainab H Almansour¹⁶, Basem H Elesawy^{17

18}, Elsayed A Elmorsy¹⁹

Affiliations

¹ Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
² Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, Saudi Arabia.
³ Central Laboratory, Theodor Bilharz Research Institute, Giza, Egypt.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, Saudi Arabia.
⁵ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Egypt.
⁶ Department of Oral and Medical Basic Sciences, Biochemistry Division, College of Dentistry, Qassim University, Buraidah, Saudi Arabia.
⁷ Department of Anatomy, College of Medicine, Qassim University, Buraidah, Saudi Arabia.
⁸ Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
⁹ Department of Anatomy, Faculty of Medicine, Cairo University, Cairo, Egypt.
¹⁰ Department of Microbiology and Immunology, College of Medicine, Qassim University, Buraidah, Saudi Arabia.
¹¹ Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah, Saudi Arabia.
¹² Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
¹³ Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia.
¹⁴ Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt.
¹⁵ Department of Family and Community Medicine, College of Medicine, Qassim University, Buraidah, Saudi Arabia.
¹⁶ Biological Sciences Department, College of Science, King Faisal University, Hofuf, Saudi Arabia.
¹⁷ Department of Pathology, College of Medicine, Taif University, Taif, Saudi Arabia.
¹⁸ Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
¹⁹ Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraidah, Saudi Arabia.

Abstract

Introduction: 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.

Methods: 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.

Results: 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, near-normal liver histology, and compelling hedgehog pathway suppression.

Discussion: 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: HMG-CoA reductase; HSP90; STA-9090; dyslipideamia; hedgehog pathway; inflammation/fibrosis.

Grants and funding

The author(s) declare that financial support was received for the research and publication of this article. The researchers would like to thank Delta University for Science and Technology, Egypt, for financial support.