STAT3 Signaling in Spinal Cord Injury: Neurochemical Mechanisms Linking Neuroinflammation, Mitochondrial Stress, and Glial Remodeling

Spinal cord injury (SCI) is a devastating neurological disorder marked by profound disturbances in cytokine signaling, redox balance, mitochondrial homeostasis, and glial-neuronal communication. Although many therapeutic strategies have been explored to attenuate secondary injury, effective molecularly targeted interventions remain limited. Increasing evidence identifies signal transducer and activator of transcription 3 (STAT3) as a central signaling node in the neurochemical response to SCI. Recent studies indicate that STAT3 exhibits pronounced spatiotemporal and cell-type-specific activation after SCI. Depending on the upstream trigger and cellular compartment involved, STAT3 can amplify or restrain neuroinflammation, shape astrocyte and microglial reactivity, influence mitochondrial bioenergetics and oxidative stress, modulate ferroptosis and apoptosis, and alter the regenerative state of the injured spinal cord. In this review, we frame STAT3 not simply as a downstream effector of the JAK/STAT cascade, but as an integrative regulator of SCI neurochemistry that links cytokine-driven signaling to metabolic stress, glial remodeling, and axonal repair. We emphasize how injury phase, cell type, and subcellular localization influence STAT3-dependent outcomes, discuss emerging therapeutic strategies that converge on STAT3-centered pathways, and outline the key challenges that must be addressed for precise translational targeting.