CORM-2 protects against sepsis-associated encephalopathy by activating the Nrf2/SLC7A11/GPX4 axis to inhibit ferroptosis and neuroinflammation.

Sepsis-associated encephalopathy (SAE) is a serious neurological complication of sepsis for which targeted pharmacological therapy remains limited. Carbon monoxide-releasing molecule-2 (CORM-2) has anti-inflammatory and antioxidant properties, but its effects on ferroptosis in SAE are incompletely understood. We investigated the protective effects and underlying mechanisms of CORM-2 in complementary in vitro and in vivo SAE models. In LPS-treated HT22 hippocampal neuronal cells, CORM-2 (50 μM) improved cell viability, reduced lipid reactive oxygen species and malondialdehyde, preserved mitochondrial membrane potential, restored glutathione and superoxide dismutase, reduced ferrous iron accumulation, and suppressed pro-inflammatory cytokines. CORM-2 also promoted nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), whereas Nrf2 knockdown markedly attenuated these effects. In an LPS-induced murine SAE model, intravenous CORM-2 (8 mg/kg) increased survival from 40 to 70%, improved neurological scores, reduced brain water content, and preserved hippocampal morphology. CORM-2 also reduced microglial activation and cerebral IL-1β, IL-6, and TNF-α. Pharmacological Nrf2 inhibition with ML385 diminished the protective effects of CORM-2, whereas the Nrf2 agonist oltipraz enhanced them. Inactive CORM-2 (iCORM-2) and DMSO vehicle did not reproduce the protective profile of active CORM-2. Collectively, these findings support a model in which CORM-2 protects against experimental SAE in association with activation of the Nrf2/SLC7A11/GPX4 axis, suppression of ferroptotic injury, and attenuation of neuroinflammation.