Simazine (SIM), a triazine herbicide and potential environmental risk factor, has been associated with neurotoxicity; however, the underlying mechanisms remain poorly characterized. Salidroside (SAL), a natural antioxidant with mitochondrial protective properties, has been reported to alleviate SIM-induced neuronal injury. Using an integrated strategy combining network toxicology and network pharmacology with experimental validation, this study systematically investigated the neurotoxic mechanisms of SIM and the neuroprotective effects of SAL. Bioinformatics analyses revealed that SIM- and SAL-related targets were significantly enriched in apoptosis- and autophagy-associated pathways. In vitro experiments demonstrated that SIM induced mitochondrial structural damage, metabolic dysfunction, and dopaminergic neuron-like SH-SY5Y cells apoptosis by inhibiting PINK1/Parkin-mediated mitophagy. Conversely, SAL effectively protected SH-SY5Y cells against SIM-induced neurotoxicity by restoring PINK1/Parkin signaling, thereby enhancing mitophagy and suppressing apoptosis. The present study elucidates the central mechanism of SIM-induced PD-like neurotoxicity in vitro and, for the first time, confirms the potential protective effect of SAL. These findings provide a novel theoretical basis for investigating nerve injury induced by SIM exposure and underscore the potential of plant-derived compounds in preventing nerve injuries related to environmental toxicants.
X et al. (Sun,) studied this question.