S100A4 exerts neuroprotective effects by attenuating blood-brain barrier disruption and oxidative stress via the PI3K/Akt/Nrf2 axis in ischemic stroke.

Ischemic stroke is a major cause of disability and mortality worldwide, with oxidative stress and blood-brain barrier (BBB) injury playing crucial roles in its pathogenesis. Our RNA sequencing results revealed that S100 calcium-binding protein A4 (S100A4) is highly expressed in the middle cerebral artery occlusion (MCAO) mouse model. We analyzed S100A4 expression in ischemic stroke patients and in mice subjected to the MCAO model. Moreover, using adeno-associated virus (AAV)-mediated knockdown of S100A4 in mice, we evaluated its effects on neurological deficits, BBB integrity, and oxidative stress in MCAO mice. Bioinformatic analyses explored the potential downstream pathways of S100A4.S100A4 expression was significantly elevated in the serum of ischemic stroke patients and brain tissues of MCAO mice. AAV-mediated knockdown of S100A4 exacerbated neurological deficits, BBB disruption, and oxidative stress in MCAO mice. The upregulation of S100A4 mitigated these outcomes, which were facilitated through the stimulation of the PI3K/Akt/Nrf2 signaling cascade.Our results illustrate that S100A4 plays a protective role in preventing neuronal damage during ischemic stroke by reducing oxidative stress and preserving BBB integrity through the PI3K/Akt/Nrf2 pathway. This highlights its promise as a potential therapeutic approach for ischemic stroke.