A strategy targeting ferroptosis for mitochondrial reprogramming and intervertebral disc degeneration therapy

<b>Background:</b> Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, yet current therapies fail to reverse the degenerative process or restore disc function. Ferroptosis, a form of iron-dependent cell death characterized by lipid peroxidation, has been implicated in IVDD progression. <b>Methods:</b> We synthesized Deferoxamine mesylate (DFOM)-loaded cerium oxide nanoparticles (DFOM@CeO₂) as a novel ferroptosis-targeting therapeutic. <b>Results:</b> DFOM@CeO₂ exhibited dual functionality by scavenging reactive oxygen species (ROS) and chelating excess iron, thereby protecting nucleus pulposus (NP) cells from ferroptosis and extracellular matrix (ECM) degradation. DFOM@CeO₂ demonstrated strong antioxidant capacity, effectively reducing iron accumulation and lipid peroxidation, and restoring glutathione peroxidase 4 (GPX4) expression in NP cells. Furthermore, DFOM@CeO₂ improved mitochondrial respiratory chain function, reduce mitochondrial ROS production and prevent mitochondrial dysfunction. In a rat model of IVDD, DFOM@CeO₂ significantly preserved disc height, reduced ECM degradation, and demonstrated superior therapeutic efficacy compared with DFOM or CeO₂ alone. Transcriptome analysis revealed that DFOM@CeO₂ modulates key ferroptosis-related genes and promotes mitochondrial reprogramming. <b>Conclusions:</b> These findings highlight DFOM@CeO₂ as a promising therapeutic strategy for IVDD, targeting both ferroptosis and mitochondrial dysfunction.