Pharmacological Inhibition of EZH2 by GSK ‐343 Attenuates Neuroinflammation in a Mouse Model of Spinal Cord Injury

Spinal cord injury (SCI) is a devastating condition with limited therapeutic options and a strong neuroinflammatory component that exacerbates tissue damage and impairs functional recovery. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and core component of the Polycomb Repressive Complex 2 (PRC2), has emerged as a key regulator of epigenetic modifications involved in neuroinflammation. In this study, we investigated the potential neuroprotective effects of GSK-343, a selective EZH2 inhibitor, in a murine model of SCI induced by extradural compression. Female adult CD1 mice received intraperitoneal injections of GSK-343 (1, 5, or 10 mg/kg) at 1- and 6-h post-injury. After 24 h, spinal cord tissues were collected and analyzed. GSK-343 treatment significantly reduced histological damage, neuronal demyelination, and the expression of pro-inflammatory markers, likely through modulation of the TRAF6/NF-κB signaling pathway. Moreover, EZH2 inhibition attenuated innate immune responses, as evidenced by the reduction in mast cell infiltration, microglial activation, and MCP-1 levels. These findings support the therapeutic potential of EZH2 inhibition as a novel epigenetic strategy to counteract neuroinflammation and promote early neuroprotection following SCI.