Zinc protects against neuroinflammation after spinal cord injury by regulating mitophagy-dependent mtDNA-cGAS-STING signaling.

Spinal cord injury (SCI) induces secondary damage characterized by mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, and chronic neuroinflammation. Cytosolic release of mitochondrial DNA (mtDNA) acts as a potent damage-associated molecular pattern (DAMP) that activates the cGAS-STING pathway and amplifies inflammation. However, the precise mechanisms by which mtDNA-driven innate immune signaling contributes to SCI pathology and how this pathway can be therapeutically modulated remain incompletely understood. In this study, we identify zinc as a dual-function regulator that preserves mitochondrial integrity and attenuates mtDNA-triggered innate immune activation after SCI. In both in vivo and in vitro models, zinc enhanced PINK1-Parkin dependent mitophagy, promoted the removal of damaged mitochondria, and stabilized mitochondrial membranes through the regulation of BAX, BAK, and VDAC1. These actions collectively reduced mtDNA leakage, thereby suppressing cGAS-STING signaling. Zinc further promoted anti-inflammatory microglial polarization and improved locomotor recovery in SCI mice. These findings uncover a previously unrecognized role of mtDNA-cGAS-STING signaling in SCI and identify zinc as a potential therapeutic candidate that restores mitochondrial-immune homeostasis to achieve neuroprotection.