Combined targeting of iron overload and BLVRA synergistically attenuates reactive astrocytes after subarachnoid hemorrhage.

Deferoxamine (DFX), a classic iron-chelating agent, has exhibited neuroprotective effects in preclinical studies of hemorrhagic stroke. However, its clinical translation remains limited, and its precise mechanisms of action in subarachnoid hemorrhage (SAH) have not been fully elucidated. This study aimed to investigate the therapeutic efficacy and underlying molecular mechanisms of DFX in a mouse model of SAH, with a particular focus on ferroptosis and astrocyte polarization. Our results demonstrated that DFX alleviated early brain injury (EBI) by reducing iron overload, oxidative stress, and ferroptosis induced by heme degradation. DFX treatment also inhibited the pathological activation of both pro-inflammatory A1 and anti-inflammatory A2 reactive astrocytes, but failed to fully suppress the overall neuroinflammatory response. Notably, biliverdin reductase A (BLVRA) was found to modulate inflammatory cytokine production via inducible nitric oxide synthase (NOS2) and TLR4 signaling, independent of astrocyte polarization. Consequently, combined treatment with DFX and siBLVRA exerted a synergistic therapeutic effect, resulting in significantly improved neurological outcomes relative to DFX monotherapy. In conclusion, DFX effectively mitigates iron-dependent ferroptosis and pathological astrocyte activation after SAH, but shows limited efficacy in controlling neuroinflammation. The enhanced anti-inflammatory effect achieved by BLVRA inhibition highlights a novel and promising therapeutic strategy that simultaneously targets iron overload and the BLVRA pathway for the treatment of SAH.