Speaker
Description
Triptolide (TP), the primary bioactive constituent of the traditional Chinese medicine Tripterygium wilfordii, is renowned for its potent pharmacological activities. However, its clinical application is severely restricted by significant hepatotoxicity. Current therapeutic strategies for TP-induced liver injury are limited. In clinical practice, TP is often co-administered with hepatoprotective agents or glucocorticoids like dexamethasone. However, those drugs often accelerate TP metabolism and potentially curtail its therapeutic duration as CYP3A4 inducers. The upregulation of CYP2E1 by TP has been identified as a critical mediator of oxidative stress and subsequent liver damage. In this study, we investigated an RNAi-based therapeutic strategy utilizing lipid nanoparticles (LNPs) to knockdown the murine Cyp2e1 gene in liver. We evaluated the hepatoprotective effects of si-Cyp2e1 LNPs in both acute and subacute murine models of TP-induced hepatotoxicity. Our results demonstrated that specific inhibition of Cyp2e1 expression significantly reduced hepatic reactive oxygen species (ROS) and malondialdehyde (MDA) levels. This was accompanied by a restoration of superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and a marked suppression of serum transaminase elevations. Transcriptomic analysis via RNA sequencing revealed that si-Cyp2e1 LNP treatment modulated the expression of genes associated with the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, a finding subsequently validated through targeted gene expression analysis. Importantly, pharmacokinetic studies showed that si-Cyp2e1 LNP administration did not alter the plasma profile of TP in mice, indicating that this hepatoprotective effect is independent of TP metabolism. Our findings suggested that RNAi-mediated targeting of CYP2E1 represented a feasible strategy for mitigating triptolide-induced hepatotoxicity.
