Abstract

HSP90 INHIBITION ALLEVIATES GLUCOCORTICOIDS-INDUCED METABOLIC, HEPATIC AND VASCULAR ABNORMALITIES

Mohammed Fulayyih Aloufi*, Sara H. Hazem, Rania R. Abdelaziz and Ghada M. Suddek

ABSTRACT

Glucocorticoids, such as dexamethasone (DEX), are frequently used for their strong anti-inflammatory actions, although they have been implicated in metabolic adverse effects such as hyperglycemia, insulin resistance, and hepatic dysfunction. This study examines the preventive role of Luminespib (Lum), a heat shock protein 90 (Hsp90) inhibitor, in reducing DEX-induced metabolic abnormalities in male Wistar rats. Rats were placed into three groups: control, DEX-only, and DEX+Lum (10 mg/kg). Over six days, DEX-treated rats showed increased fasting glucose levels, decreased insulin secretion, poor glucose tolerance, and raised liver enzymes (ALT and AST), considerable body weight loss, and histological changes in hepatic and aortic tissues. However, co-administration of Lum greatly enhanced insulin levels and glycemic management, as evidenced by better oral glucose tolerance test (OGTT) outcomes and a lower glucose area under the curve (AUC). Lum therapy also reduced the increase in liver enzyme levels, minimized body weight loss, and restored DEX-induced structural damage in hepatic and aortic tissues. Histological investigation revealed that Lum addition reduced steatosis and vascular anomalies. These results indicate that Lum efficiently counteracts the metabolic and inflammatory damage triggered by DEX. This demonstrates the possibility of Hsp90 inhibition as an additional therapeutic approach for improving the safety and efficacy of glucocorticoid-based therapies for chronic inflammatory and autoimmune diseases.

Keywords: Dexamethasone; Luminespib; Hsp90; metabolic disorder; hepatic abnormalities; vascular abnormalities.