Hydrogen Sulfide Modulates Microglial Polarization and Remodels the Injury Microenvironment to Promote Functional Recovery After Spinal Cord Injury

ABSTRACT Aims Spinal cord injury (SCI) disrupts tissue homeostasis, leading to persistent neuroinflammation and scar formation that severely impedes functional recovery. Current therapeutic approaches are insufficient to address these challenges. In this study, we investigated whether exogenous hydrogen sulfide (H 2 S) can modulate neuroinflammatory responses and remodel the injury microenvironment to promote tissue repair and restore motor function following SCI. Methods T10 crush SCI was induced in mice, followed by daily intraperitoneal administration of the H 2 S donor anethole trithione (ADT). Immunofluorescence staining, tissue clearing, western blotting, and behavioral assessments were performed to evaluate scar formation, vascular regeneration, neuronal survival, and motor function. Results ADT‐based H 2 S therapy significantly promoted wound healing, inhibited scar formation, enhanced vascular regeneration, and protected residual neurons and axons from secondary injury. Mechanistically, H 2 S suppressed microglial proliferation and activation, promoting their polarization toward an anti‐inflammatory phenotype and alleviating neuroinflammation. Consequently, motor function recovery was markedly improved. Conclusion H 2 S modulates microglial activation and mitigates neuroinflammation, establishing a permissive microenvironment for SCI repair and significantly enhancing motor function recovery. Given ADT's established clinical safety and its effective gasotransmitter properties, our findings underscore its immediate translational potential for treating SCI.