Pterostilbene Attenuates Neuronal Ferroptosis After Traumatic Brain Injury: Involvement of the SIRT1/PGC-1α/NRF2 Signaling Pathway.

Ferroptosis is increasingly recognized as a key driver of neurological damage following traumatic brain injury (TBI). Pterostilbene (PTE), a natural dimethylated analog of resveratrol, possesses superior blood-brain barrier (BBB) permeability and potent antioxidant properties, suggesting therapeutic potential for neurological disorders. However, the specific role and underlying mechanisms of PTE in TBI-induced ferroptosis remain largely unexplored. In the present study, we demonstrate that PTE treatment significantly ameliorates TBI pathology, as evidenced by reduced lesion volume, attenuated neuronal loss, and improved neurological recovery. We further confirm that PTE suppresses ferroptosis in a GPX4-dependent manner, a finding validated across both in vivo TBI mouse models and in vitro erastin-induced HT22 cell models. Mechanistically, PTE enhances resistance to ferroptosis through the engagement of the SIRT1/PGC-1α signaling pathway. Specifically, we found that PGC-1α is closely associated with the recruitment of nuclear NRF2 to the Gpx4 promoter region, co-activating its transcription and subsequently inhibiting ferroptosis. Clinical data further support these findings, revealing that higher expression levels of SIRT1 and PGC-1α correlate with favorable long-term outcomes in TBI patients, as assessed by the Glasgow Outcome Scale (GOS). Collectively, our results provide novel insights into the neuroprotective mechanisms of PTE and support its clinical potential in mitigating neuronal ferroptosis after TBI.