Salidroside regulates hippocampal neuronal autophagy in ASD mice via the SIRT2/FoxO1 pathway

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by neuronal dysfunction and impaired autophagy. Salidroside (SAL), a bioactive component derived from Rhodiola, exhibits neuroprotective activity; however, its effects and mechanisms in ASD remain largely unknown. Here, we examined the effects of SAL on valproic acid (VPA)-induced neuronal injury and ASD-related behaviors and assessed the role of the sirtuin 2 (SIRT2)/forkhead box O1 (FoxO1) pathway. VPA-induced HT22 cell injury models and ASD mouse models were used in this study. HT22 cells were exposed to 2mM VPA and treated with 20μM SAL, with AGK2 applied for SIRT2 inhibition. ASD mice received SAL administration from postnatal day 21 for 14 days, and AK-7 was used to further evaluate SIRT2 involvement. VPA exposure decreased HT22 cell viability, caused neuronal damage, increased autophagosome accumulation, and induced ASD-like behaviors in mice, including impaired social interaction, enhanced repetitive grooming, and reduced exploratory activity. SAL treatment improved cell viability, alleviated neuronal damage, attenuated autophagy-related changes, and improved behavioral abnormalities, whereas these effects were partially blocked by AGK2 or AK-7. Furthermore, SAL reversed VPA-induced alterations in autophagy-related proteins, including decreased Beclin-1 and LC3 expression and increased p62 expression, while restoring SIRT2, FoxO1, NeuN, and MAP2 levels and reducing the Ac-FoxO1/FoxO1 ratio in HT22 cells and hippocampal tissues. These findings indicate that SAL protects against VPA-induced neuronal injury and ASD-related behavioral deficits, which are associated with changes in the SIRT2/FoxO1 pathway and autophagy-related processes.