Treatment of early brain injury after subarachnoid hemorrhage in the rat model by inhibiting p53-induced ferroptosis.

Post-subarachnoid hemorrhage (SAH) survivors experience severe neurological disability. Previous studies implicate that ferroptosis is involved in SAH. Ferroptosis is an iron-dependent form of regulated cell death caused by the accumulation of lipid peroxidation. However, the role and the mechanism of ferroptosis in SAH are still uncertain and need further study. Thus, we investigated the effect of ferroptosis on early brain injury (EBI) after SAH and further clarified its mechanism. The results showed ferroptosis characteristics appeared in the cerebral cortex of rats with SAH after 24 h. However, ferroptosis could be rescued by Ferrostatin-1 (Fer-1). Treatment with Fer-1 could increase SLc7a11 and GPx4, and alleviated damage-associated molecular pattern molecules and inflammatory cytokines. Similarly, blood-brain barrier impairment, brain edema, behavioral deficits and neuronal damage were reduced by inhibiting ferroptosis. More importantly, the p53 inhibitor pifithrin-α could significantly block cortical SAH-induced ferroptosis. Collectively, these results indicated that ferroptosis aggravated EBI after SAH was partly dependent on p53, and inhibiting ferroptosis might be an effective therapeutic target for EBI.