Abstract
BACKGROUND: Cerebral ischemia/reperfusion injury can induce nerve cell apoptosis and ferroptosis and activation of the neuroinflammatory cascade plays a critical role in ischemic stroke progression. Mesenchymal stem cells (MSCs) can aid in repairing nerve injuries and regulating inflammatory responses, but their roles in ischemic stroke are unknown. METHODS: Here, we investigate the impact of microglial susceptibility to ferroptosis on neuronal apoptosis using an oxygen-glucose deprivation/reperfusion (OGD/R) model. Furthermore, we examined the effects of hypoxia-preconditioned olfactory mucosa mesenchymal stem cells (hOM-MSCs) on attenuating microglial ferroptosis and improving neuroinflammatory response in models of OGD/R and middle cerebral artery occlusion (MCAO). RESULTS: Firstly, it has been confirmed that the susceptibility of microglial to ferroptosis significantly amplifies their neuroinflammatory response, thereby accelerating neuronal apoptosis in the OGD/R model. A functional assay identified that the core functional factor, peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), secreted from hOM-MSCs has a critical role in the hOM-MSC-modulated recovery of cellular activity in neurons. This discovery was accomplished through inhibiting microglia ferroptosis and the enhancement of immune regulation in the area affected by an infarct, all of which are closely linked to neuroinflammatory reactions. Mechanistically, exposure to hOM-MSCs partially mediates the amelioration of neuroinflammatory response and restoration of neural function in ischemic stroke by means of PGC-1α activation within the infarct region, via initiation of the PPARα-GPX4/ACSL4-NFκB signaling cascades in microglia. CONCLUSIONS: These findings provide convincing proof that PGC-1α plays a crucial role in facilitating the advantageous impacts of hOM-MSCs on the enhancement of neural functionality following an ischemic stroke. The treatment of hOM-MSC could be a promising and effective neuroprotective candidate to ischemic stroke, and PGC-1α may be used in isolation or in combination with hOM-MSCs for ischemic stroke treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07240-5.