Hydrogen Attenuates Oxidative Damage via NRF2-Mediated Mitophagy after Subarachnoid Hemorrhage

Mitochondrial dysfunction is recognized as a central pathological mechanism in subarachnoid hemorrhage (SAH). This study aimed to investigate whether mitophagy serves as a key mechanism by which hydrogen (H₂) exerts its antioxidative effects following SAH.

Using in vivo (mouse SAH model) and in vitro (HT22 cell SAH model) approaches, we demonstrated that H₂ inhalation significantly improved neurological function and alleviated oxidative stress and apoptosis. Mechanistically, H₂ maintained mitochondrial membrane potential and functional integrity by enhancing phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. RNA sequencing and functional assays identified nuclear factor erythroid 2-related factor 2 (NRF2) as the key upstream target. H₂ promoted NRF2 nuclear translocation and activated the antioxidant pathway. Dual-luciferase reporter assays further confirmed that NRF2 directly binds to and activates the PINK1 promoter. Pharmacological inhibition of NRF2 (ML385) or mitophagy (Mdivi-1) abolished the protective effects of H₂, confirming that the NRF2-PINK1/Parkin axis is central to the effect of H₂.

The present study clearly establishes the NRF2-PINK1/Parkin axis as a key mechanism underlying the neuroprotective effect of H₂ in SAH. This study connects mitochondrial quality control with endogenous antioxidant systems, suggesting H₂ administration as a potential mitochondrion-targeted clinical intervention.

The NRF2-PINK1/Parkin axis is a novel and key mechanism underlying the neuroprotective effect of H₂ in SAH. This finding advances our understanding beyond general antioxidant theories by demonstrating a specific, multistep molecular cascade. H₂ administration is a potential mitochondrion-targeted intervention with strong implications for clinical translation in SAH patients. Antioxid. Redox Signal. 44, 443-463.