A novel combination therapy targets sonic hedgehog signaling by the dual inhibition of HMG-CoA reductase and HSP90 in rats with non-alcoholic steatohepatitis
Non-alcoholic steatohepatitis (NASH) is marked by liver inflammation, fat buildup, and collagen deposition. Due to the scarcity of effective treatments, there is an urgent need for innovative therapeutic approaches. Given the disease’s complexity, combination therapies are crucial. Hedgehog signaling has been implicated in promoting NASH, with cholesterol influencing this pathway by altering PTCH1 conformation and SMO activity. HSP90 also plays a key role in stabilizing SMO and GLI proteins. We discovered strong positive correlations between Hedgehog signaling proteins (Shh, SMO, GLI1, GLI2) and both cholesterol and HSP90 levels. In this study, we explored the novel combination of the cholesterol-lowering agent lovastatin Zelavespib and the HSP90 inhibitor PU-H71, both in vitro and in vivo. This combination showed a synergy score of 15.09 and an MSA score of 22.85, as determined by the ZIP synergy model based on HepG2 cell growth inhibition rates. In a NASH rat model induced by thioacetamide and a high-fat diet, the combination therapy extended survival, improved liver function and histology, and boosted antioxidant defenses. Additionally, it demonstrated anti-inflammatory and anti-fibrotic effects by modulating TNF-α, TGF-β, TIMP-1, and PDGF-BB levels, with notable suppression of Col1a1 gene expression, hydroxyproline, and α-SMA. These promising results may be linked to the combination’s ability to inhibit key Hedgehog signaling molecules. In conclusion, investigating this combination offers valuable insights and holds potential for better management of NASH and other fibrotic conditions.