Progranulin alleviates cerebral ischemia-reperfusion-induced neuronal ferroptosis via regulating p-STAT3/HSPA5...

Progranulin (PGRN) exerts neuroprotective effects. However, the roles of PGRN in cerebral ischemia/reperfusion (I/R) injury have not been reported.

This study aimed to investigate the potentials of PGRN in cerebral ischemia injury.

Middle cerebral artery occlusion/reperfusion (MCAO/R) surgery was used to establish mouse cerebral ischemia/reperfusion (I/R) injury model. Neuronal loss was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. HT22 cells were exposed to oxygen-glucose deprivation/reoxygenation to establish an in vitro cerebral I/R model. Gene expression was detected using reverse transcription-quantitative PCR, immunofluorescence, and Western blot. Oxidative stress was detected using reactive oxygen species and malondialdehyde assays. Iron metabolism was detected using ferrous iron assay. Neuronal functions were determined using Cell Counting Kit-8 and propidium iodide staining assay. Signal transducer and activator of transcription 3 (STAT3) and heat shock protein family A member 5 (HSPA5) interaction was determined using dual-luciferase reporter and chromatin immunoprecipitation assays.

Cerebral I/R injury contributed to neuronal ferroptosis. PGRN was downregulated in cerebral I/R injury in vivo and in vitro, the overexpression of which inhibited oxidative stress and neuronal ferroptosis. PGRN promoted the hyperactivation of STAT3, which transcriptionally upregulated HSPA5 signaling. However, STAT3 knockdown abolished the effects of PGRN overexpression and promoted oxidative stress and neuronal ferroptosis.

In summary, PGRN protected neurons from the cerebral I/R injury-induced ferroptosis via activating p-STAT3/HSPA5 signaling. Therefore, PGRN may be a therapeutic target for cerebral I/R injury.