Removal or inhibition of transglutaminase 2 decreases cellular stress, supporting tissue preservation, and recovery after SCI.

Transglutaminase 2 (TG2) is a multifunctional enzyme widely implicated in neuroinflammation and extracellular matrix (ECM) remodeling after central nervous system (CNS) injury and diseases. In spinal cord injury (SCI), TG2 contributes significantly to pathology through ECM remodeling and glial scar formation. Here, we explored the intracellular roles of TG2 following severe spinal cord compression injury, utilizing TG2 knockout (KO) mice and pharmacological inhibition via cystamine. Genetic deletion or inhibition of TG2 significantly improved locomotor function and promoted enhanced preservation of white and gray matter post-injury. Mechanistically, TG2 KO reduced fibronectin deposition, chondroitin sulfate proteoglycan accumulation, and reactive gliosis. Importantly, imaging mass cytometry revealed that TG2 deletion attenuated cellular stress responses, including reductions in ER stress markers (GRP78), oxidative stress mediators (pNrf2), mitochondrial dysfunction indicators (BNIP3 and cytochrome c), and increased neuronal expression of survival-associated (pREL-NFκB). These results highlight a novel intracellular function for TG2 in exacerbating neurodegeneration through modulation of cellular stress pathways, offering promising therapeutic implications for SCI recovery.