ABSTRACT Ferroptosis is one of the important mechanisms of secondary neuronal death after spinal cord injury (SCI). However, the upstream regulators that could be targeted for therapeutic intervention remain poorly defined. This study identifies gamma‐glutamyl transferase 1 (GGT1) as a key driver of ferroptosis, upregulated in neurons post‐SCI. Screening a 150‐compound natural product library, we discovered Enocyanin (EA), which reduced GGT1 protein levels, protected neurons from hypoxic injury, and exhibited anti‐ferroptotic effects. Mechanistically, EA promoted GGT1 degradation through the E3 ligase MGRN1, leading to K48‐linked polyubiquitination and proteasomal clearance, halting ferroptosis. To improve EA's stability and delivery, we engineered a biomimetic nanoplatform (NSCm@EA) using neural stem cell membranes, enhancing drug accumulation at the injured spinal cord. At single‐cell resolution, NSCm@EA was shown to precisely remodel neuronal subpopulations, selectively expanding γ‐motor neurons and upregulating synaptic genes such as Gria2 and Negr1, while suppressing inflammatory and oxidative stress pathways. In summary, this study reveals GGT1's role in ferroptosis, identifies a natural product that induces its ubiquitin‐mediated degradation, and presents a targeted biomimetic delivery strategy for precise intervention in spinal cord injury.
Yang et al. (Thu,) studied this question.