Luminespib protects against dexamethasone-induced hepatic, vascular, and metabolic abnormalities in rats.

Luminespib (LUM), a novel HSP90 inhibitor, has demonstrated promising effects in the oncology domain. However, no studies have explored the protective effects of LUM against dexamethasone (DEX)-induced metabolic and vascular toxicity, which provides an innovative approach to research. Adult male Wistar rats were intoxicated with DEX (8 mg/kg, i.p., q.d., for 6 days). In treatment groups, LUM was administered in two doses (2.5 and 5 mg/kg, i.p., q.o.d., for 6 days) 1 h before DEX administration. The results demonstrated that DEX-induced hepatic steatosis (NAFLD score), elevated liver enzymes (ALT, AST & LDH), aortic injury (aorta dissection score), and metabolic abnormalities (fasting insulin & OGTT) were significantly ameliorated by LUM treatment. According to our results, such outstanding improvements were attributed to (i) restoring cellular oxidant balance (GSH, MDA & NO), (ii) curbing NF-κB/TNF-α/MCP-1 inflammatory cascade, (iii) HSP90 inhibition with reduced expression of glucocorticoid receptors (GR), (iv) reduced expression of the endoplasmic reticulum stress sensors (CHOP & PERK), (v) activation of protein degradation pathways that degrade the misfolded GR including proteasomal degradation (20 S proteasome) and autophagy (BECLIN1). In conclusion, the findings in this study provide valuable insights into the therapeutic potential of LUM in protecting against DEX-induced deleterious effects on hepatic and aortic tissue in order to get the optimum therapeutic outcome from DEX.