Hinokitiol Promotes Neural Repair After Spinal Cord Injury by Reprogramming Microglial Inflammatory and Redox Responses

Secondary neuroinflammation and oxidative stress, driven partly by maladaptive microglial activation, limit recovery after spinal cord injury (SCI). We investigated whether hinokitiol promotes neural repair and whether nuclear factor erythroid 2-related factor 2 (Nrf2) signaling mediates its effects. Male C57BL/6J mice received T10 contusive SCI and intraperitoneal vehicle or hinokitiol (20 mg/kg once daily for 7 days, starting 6 h after injury). Locomotor, electrophysiological, histological, and single-nucleus transcriptomic outcomes were evaluated. In vitro, lipopolysaccharide-challenged BV2 microglia, BV2–HT22 indirect cocultures, and pharmacological Nrf2 inhibition with ML385 were used to examine inflammatory, oxidative, and neuronal apoptosis outcomes. Hinokitiol improved locomotor and motor-evoked potential outcomes; reduced lesion cavitation, collagen deposition, neuronal loss, demyelination, and astroglial activation; and shifted microglia from inflammatory/oxidative programs toward repair-associated states. Hinokitiol reduced tumor necrosis factor-α, interleukin-1β, interleukin-6, inducible nitric oxide synthase, cyclooxygenase-2, and NADPH oxidases 2/4 in spinal cord tissue and BV2 cells. Hinokitiol-pretreated microglia reduced HT22 apoptosis in coculture. Hinokitiol decreased Kelch-like ECH-associated protein 1 and increased Nrf2 and heme oxygenase-1, whereas ML385 attenuated these effects and restored inflammatory and oxidative responses. Hinokitiol supports neural repair after SCI by reprogramming microglial inflammatory-redox states, at least partly through Nrf2 signaling. These findings justify further pharmacokinetic, sex-inclusive, and long-term safety studies.