Hedyotis Diffusae Herba Mitigates Rotenone-Induced Neurotoxicity via Akt Pathway in SH-SY5Y Cells

Hedyotis Diffusae Herba (HDH), known in traditional Chinese medicine for its heat-clearing and detoxifying properties, has been widely used to manage inflammation-related conditions. However, its neuroprotective potential and mechanism in the context of Parkinson’s disease (PD) remain unclear.Network pharmacology and molecular docking were applied to predict the interactions between HDH components and PD-associated targets. Molecular dynamics simulations assessed the binding stability of major compounds to core targets. Rotenone-induced SH-SY5Y cell injury served as an in vitro PD model to evaluate HDH’s biological effects. Cell viability, reactive oxygen species (ROS), IL-6 secretion, and Akt phosphorylation were assessed by CCK-8 assay, ROS detection kit, ELISA, and western blot, respectively. MK2206, an Akt inhibitor, was used to validate pathway involvement.Seven bioactive compounds were identified in HDH, among which stigmasterol and quercetin exhibited strong binding affinities with AKT1, IL-6, and JUN. Simulations confirmed stable interactions. HDH significantly increased cell viability and decreased intracellular ROS and IL-6 levels in rotenone-treated SH-SY5Y cells. Akt phosphorylation was restored by HDH, and the effect was blocked by MK2206, indicating Akt pathway participation.HDH exerts neuroprotective effects against rotenone-induced toxicity via antioxidant and anti-inflammatory activities and Akt pathway activation. These findings provide mechanistic insight and pharmacological support for HDH as a potential candidate in complementary therapy for PD.