# TRIM14 Inhibition Suppresses Microglial Polarization and Pyroptosis Through the NF-κB/NLRP3 Pathway to Enhance Spinal Cord Injury Repair

## TL;DR

This study shows that inhibiting TRIM14 reduces harmful inflammation and improves recovery after spinal cord injury by targeting the NF-κB/NLRP3 pathway.

## Contribution

The study identifies TRIM14 as a novel regulator of microglial polarization and pyroptosis in spinal cord injury.

## Key findings

- TRIM14 knockdown suppresses NF-κB activation and microglial M1 polarization.
- AAV-CRISPR/CasRx-mediated TRIM14 silencing improves axonal regeneration and locomotor function in SCI rats.
- TRIM14 inhibition reduces NLRP3-mediated pyroptosis and neuroinflammation.

## Abstract

Spinal cord injury (SCI) triggers severe neuroinflammation, impeding recovery. While microglial M1 polarization and pyroptosis are key drivers, their upstream regulators are incompletely understood. This study investigated the role of the ubiquitin ligase tripartite motif-containing protein 14 (TRIM14) in regulating neuroinflammation following SCI. Using rat SCI models and BV2 microglia exposed to lipopolysaccharide (LPS), we assessed TRIM14 expression and its functional impact via knockdown and overexpression, alongside pharmacological neurofilament (NF)-κB inhibition (pyrrolidine dithiocarbamate [PDTC]). TRIM14 was upregulated in injured spinal cords and microglia, associated with injury severity. TRIM14 knockdown in microglia stabilized IκBα by inhibiting its ubiquitination, thereby suppressing NF-κB activation, M1 polarization, and NLRP3-mediated pyroptosis. Conversely, TRIM14 overexpression exacerbated inflammation, effects markedly reversed by PDTC. In SCI rats, intralesional AAV-CRISPR/CasRx-mediated TRIM14 silencing significantly attenuated neuroinflammation and neuronal apoptosis, enhanced axonal regeneration, and improved locomotor function. Mechanistically, TRIM14 knockdown suppressed NF-κB/NLRP3 signaling, promoting a prorepair microenvironment. These results identify TRIM14 as a critical regulator of microglial activation and pyroptosis post-SCI, suggesting its therapeutic targeting could be a viable strategy to promote neural repair.