<p>Spinal cord injury (SCI) is a highly disabling condition affecting the central nervous system (CNS). Neuroinflammation and neuronal apoptosis are two critical factors in the pathological process of SCI. Although electroacupuncture (EA) has been reported to alleviate neuroinflammation in brain injury, the underlying molecular mechanism remains unclear. Transcriptome sequencing of spinal cord tissues was performed to identify potential key factors and pathways involved in EA post-SCI. DHCR24, a cholesterol synthesis regulator, was selected as a key candidate and DHCR24 was downregulated after SCI (log₂FC = -1.6, <i>P</i> &lt; 0.01), and this downregulation was notably reversed by EA treatment (log₂FC = 1.04, <i>P</i> &lt; 0.01). We investigated the neuroprotective effect of DHCR24 against neuron death and neuroinflammation in SCI, with a particular focus on its effects on the Wnt signaling pathway. SCI-induced DHCR24 downregulation was associated with decreased expression of the axonal regeneration marker NF and increased activation of Iba1/CCR7-positive microglia, accompanied by enhanced neuronal apoptosis and inflammatory factor release. Importantly, functional validation experiments demonstrated that DHCR24 was required for the therapeutic effects of EA. Complementary in vitro studies in LPS/IFN-γ-stimulated BV2 microglia cells confirmed the role of DHCR24 in microglial polarization and neuronal survival, likely via Wnt signaling activation. Integrating transcriptomic and mechanistic evidence, we demonstrate that DHCR2 promotes Wnt pathway activation, reduces neuronal apoptosis and neuroinflammation, and ultimately enhances spinal cord repair. This study provides evidence supporting the potential clinical application of EA in SCI recovery and identifies DHCR24 may be a key mechanistic target underlying its therapeutic effects.</p> Graphical Abstract <p></p>