Ubiquitin-specific protease 14 inhibition promotes mitophagy and attenuates neural apoptosis after spinal cord injury.

Spinal cord injury (SCI) is a devastating condition characterized by severe neurological deficits and limited recovery, primarily due to the intricate cascade of secondary injury mechanisms. Post-SCI mitochondrial dysfunction can lead to increased oxidative stress and neuronal apoptosis. This study aimed to investigate whether inhibition of USP14 could enhance mitophagy, thereby counteracting apoptosis and providing effective neuroprotection both in vitro and in vivo after SCI. Pharmacological and genetic approaches were employed to inhibit USP14 in rat models of SCI and in HT-22 neuronal cells subjected to oxygen-glucose deprivation (OGD). The results revealed that USP14 inhibition significantly reduced neuronal apoptosis by modulating mitochondrial apoptotic pathways and preserving mitochondrial content, subsequently alleviating neurological deficits associated with SCI. Enhanced autophagic flux induced by USP14 inhibition facilitated selective clearance of damaged mitochondria, offering substantial protection to neurons and promoting functional motor recovery. Blocking mitophagy with 3-MA reversed these protective effects, underscoring the critical role of mitophagy in the neuroprotective outcomes mediated by USP14 inhibition. Collectively, our findings suggest that inhibiting USP14 enhances mitophagy, maintains mitochondrial function, and reduces neuronal apoptosis, thereby protecting neurons and improving motor function post-SCI. These results highlight USP14 as a promising therapeutic target for early intervention strategies in SCI through the modulation of mitochondrial function and enhancement of mitophagy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-31745-0.