Low-intensity pulsed ultrasound promotes peripheral nerve regeneration by alleviating Schwann cells pyroptosis.

Peripheral nerve injury (PNI), a common clinical condition, heavily relies on the functional condition of Schwann cells (SCs) for effective repair. Emerging evidence shows that excessive pyroptosis of SCs hinders neural regeneration. Low-intensity pulsed ultrasound (LIPUS), a non-invasive physical therapy, shows potential in tissue repair; however, its role in regulating SCs pyroptosis remains unclear. This study explores the mechanism by which LIPUS improves PNI recovery by reducing SCs pyroptosis. We find that LIPUS significantly enhances motor function recovery, promotes axonal regeneration and remyelination, and decreases gastrocnemius muscle atrophy through a rat sciatic nerve crush model. LIPUS biomechanically mitigates mitochondrial dysfunction in SCs, thereby suppressing the NLRP3/Caspase-1/GSDMD-N pyroptosis signaling pathway. This inhibition reduces IL-1β and IL-18 release, boosting SCs proliferation, migration, and clearance of myelin debris, collectively fostering a regenerative microenvironment that supports axonal regrowth, remyelination, and functional recovery. Our results demonstrate a mechanobiological mechanism by which LIPUS promotes peripheral nerve regeneration through alleviating pyroptosis, providing a promising therapeutic approach for PNI.