Urolithin A promotes peripheral nerve regeneration via TFEB-mediated mitophagy and NLRP3 inflammasome suppression

Peripheral nerve injury (PNI) often results in incomplete recovery due to persistent neuroinflammation and mitochondrial dysfunction. Here, we investigated the therapeutic potential of Urolithin A (UA), a gut microbiota-derived metabolite, in promoting nerve regeneration by modulating mitophagy and inflammasome activation.

To evaluate whether UA enhances peripheral nerve regeneration by activating TFEB-mediated mitophagy and inhibiting NLRP3 inflammasome activation.

In a rat sciatic nerve crush injury model and Schwann cell cultures, UA effects were evaluated using behavioral tests, histological analysis, transmission electron microscopy, immunofluorescence, Western blotting, and molecular docking.

UA administration significantly improved sciatic functional index, reduced muscle atrophy, and enhanced axonal regeneration and remyelination. Mechanistically, UA promoted transcription factor EB (TFEB) nuclear translocation, upregulated autophagy-lysosomal genes, and facilitated clearance of damaged mitochondria, leading to reduced ROS levels and suppression of NLRP3 inflammasome activation. These effects were abolished by TFEB knockdown or autophagy inhibition, indicating a TFEB-dependent mechanism. Molecular docking suggested direct binding between UA and TFEB.

UA facilitates peripheral nerve repair by coupling TFEB-mediated mitophagy with NLRP3 inflammasome inhibition. This dual action provides a promising non-invasive therapeutic strategy for PNI and warrants further translational research.