An FGF21-based fusion protein ameliorates mitochondrial dysfunction and promotes recovery post spinal cord injury.

Mitochondrial dysfunction and defective repair are central drivers of secondary injury following spinal cord injury (SCI), yet effective strategies to restore mitochondrial quality control remain limited. Here, we develop an engineered long-acting fibroblast growth factor 21 fusion protein (SFGF21) by incorporating a linker peptide to enhance molecular targeting and oxidative stability. In a mouse model of SCI, sustained delivery of SFGF21 specifically potentiated dynamic crosstalk between mitochondria and lysosomes, thereby activating the BNIP3/BNIP3L pathway-mediated mitophagic flux and clearing dysfunctional mitochondria in injured neurons. This process restored mitochondrial homeostasis, suppressed lipid peroxidation, and alleviated oxidative stress in injured neurons. Loss-of-function experiments confirmed that both FGFR1 and BNIP3 are required for SFGF21-induced mitophagy and neuroprotection. Together, our findings establish engineered modulation of organelle crosstalk as a therapeutic strategy to activate mitophagy and support neural repair after SCI, highlighting mitochondria-targeted protein engineering as a potential therapeutic path for spinal cord repair.