Ischemic stroke (IS) is a leading cause of disability and mortality worldwide, with a rising incidence among younger populations. Effective neuroprotective therapies remain limited. Piperine (PIP), a bioactive alkaloid derived from Piper nigrum L., has demonstrated neuroprotective potential. However, its underlying mechanisms are not fully understood. This study investigated the protective effects of PIP against ischemic stroke and its role in regulating autophagy via the PI3K/AKT/mTOR signaling pathway. A permanent middle cerebral artery occlusion (pMCAO) model was established in male Sprague–Dawley rats, and ischemic injury was induced in HT22 cells using oxygen–glucose deprivation (OGD). Neurological function, infarct volume, neuronal morphology, and ultrastructural alterations were assessed in vivo, while cell viability and protein expression were evaluated in vitro. We found that PIP treatment, particularly at a dose of 30 mg/kg, significantly improved neurological outcomes, reduced infarct volume, and attenuated neuronal and ultrastructural damage in pMCAO rats, with effects comparable to nimodipine. Mechanistically, PIP markedly inhibited the phosphorylation of PI3K, AKT, and mTOR and downregulated the autophagy-related proteins Beclin1 and LC3-II in ischemic brain tissue. Consistent neuroprotective effects and molecular changes were also observed in OGD-injured HT22 cells. These findings indicate that PIP exerts neuroprotective effects in ischemic stroke by suppressing excessive neuronal autophagy through modulation of the PI3K/AKT/mTOR signaling pathway, highlighting its potential therapeutic value for ischemic stroke.

Piperine, Brain Ischemic Stroke, Neuroprotective, Autophagy, PI3K/AKT/mTOR Pathway