Valproic acid boosts hair follicle stem cell resilience to oxygen-glucose deprivation through autophagy induction and AKT/mTOR suppression.

Stem cell-based therapy represents a promising strategy for the treatment of ischemic stroke. However, its therapeutic efficacy is limited by the poor survival and migration of transplanted stem cells within the hostile ischemic microenvironment. In this study, we investigated whether preconditioning human hair follicle-derived stem cells (HFSCs) with valproic acid (VPA) could enhance their survival and migration under ischemic-like conditions, with a particular focus on the roles of autophagy and the AKT/mTOR signaling pathway. HFSCs were pretreated with 1 mM VPA for 24, 72, or 168 h and then exposed to oxygen-glucose deprivation (OGD) as an in vitro model of ischemic injury. Rapamycin (RAPA), a known autophagy inducer, served as a positive control. VPA pretreatment significantly enhanced autophagic activity, as indicated by increased expression of Beclin 1 and LC3-II, decreased p62 accumulation, and augmented lysosome biogenesis. Concurrently, VPA suppressed the AKT/mTOR signaling pathway. These effects conferred protection against OGD-induced apoptosis and preserved cell viability. Notably, 72 h VPA preconditioning markedly improved the migration capacity of HFSCs under OGD conditions. Importantly, the cytoprotective and pro-migratory effects of VPA were abolished by chloroquine (CQ), an autophagy inhibitor, highlighting the essential role of autophagy in mediating these benefits. In conclusion, our findings demonstrate that VPA preconditioning enhances the survival and migration of HFSCs through autophagy activation and inhibition of the AKT/mTOR pathway. These results suggest that autophagy-based preconditioning strategies may improve the efficacy of stem cell therapies for ischemic stroke and warrant further translational research.