Omaveloxolone promotes functional recovery of spinal cord injury by reducing inflammatory response and regulating macrophage polarization.

BACKGROUND: Spinal Cord Injury (SCI) is a severe central nervous system disorder that initiates inflammatory reactions, exacerbating tissue damage and impeding neuronal repair. Macrophage polarization plays a critical role in this pathological process: it significantly regulates inflammation resolution and tissue regeneration, rendering its modulation a key strategy for SCI repair. Omaveloxolone (Omav), a novel Nrf2 activator, has demonstrated potential in regulating inflammatory responses, suggesting it may serve as a promising candidate for SCI intervention. METHODS: To evaluate the efficacy and underlying mechanism of Omav in SCI repair, a spinal cord contusion model was established in animal subjects. Additionally, an in vitro lipopolysaccharide (LPS)-induced macrophage polarization model was constructed to further validate Omav's effects on macrophage phenotypes. RNA sequencing (RNA-seq) was employed to elucidate the molecular pathways through which Omav modulates post-SCI pathophysiology. RESULTS: In vivo experiments revealed that Omav effectively restored motor function in SCI-induced animals. RNA-seq analysis further demonstrated that Omav reshaped inflammatory cascades following SCI, with a significant impact on macrophage polarization dynamics. Specifically, Omav promoted the formation of an M2-dominant macrophage landscape (a phenotype associated with anti-inflammation and tissue repair) while reducing the pro-inflammatory M1 macrophage phenotype. These findings were corroborated by in vitro studies, which confirmed that Omav directly facilitated M2-type macrophage polarization. CONCLUSION: Our results collectively confirm the efficacy of Omav in repairing spinal cord injury by targeting macrophage polarization and regulating inflammatory responses. This study not only highlights the therapeutic potential of Omav for SCI but also provides a novel pharmacological strategy for SCI treatment.