Bidirectional regulation of neuronal autophagy in ischemic stroke: Mechanisms and therapeutic potential

Ischemic stroke, characterized by cerebral blood flow disruption, triggers complex pathophysiological responses where neuronal autophagy plays a bidirectional regulation role in neuroprotection and injury. Autophagy, activated by energy deprivation, hypoxia, and endoplasmic reticulum stress, dynamically regulates neuronal survival through selective autophagy (e.g., mitophagy, endoplasmic reticulum-phagy, ferritinophagy) of damaged organelles and protein aggregates. Early-stage moderate autophagy exerts neuroprotection by clearing cytotoxic aggregates and maintaining metabolic homeostasis, while excessive or prolonged autophagy exacerbates neuronal death via energy depletion and activation of apoptosis/ferroptosis pathways. Key regulatory mechanisms involve AMPK/mTOR, PI3K/AKT, HIF-1, and MAPK signaling, which modulate autophagic flux and crosstalk with oxidative stress, inflammation, and mitochondrial dynamics. Notably, selective autophagy pathways exhibit spatiotemporal specificity: mitophagy via PINK1/Parkin and BNIP3/FUNDC1 balances mitochondrial quality control, while ferritinophagy-mediated iron dysregulation drives ferroptosis. Pharmacological interventions targeting autophagy-related pathways (e.g., rapamycin, 3-MA, NCOA4 inhibitors) or natural compounds (e.g., Ginkgolide B, HSYA) demonstrate therapeutic potential by fine-tuning autophagic activity. However, challenges remain in defining optimal autophagy thresholds and translating preclinical findings to clinical applications. This review highlights the critical importance of spatiotemporal regulation of neuronal autophagy to develop precise neuroprotective strategies for ischemic stroke, with a particular focus on the interaction between autophagy modulators and the pathophysiological mechanisms of ischemia.