The nuclear receptor transcription factors NR2F1 and NR2F6 promote corticospinal tract regeneration and functional motor recovery after spinal cord injury through complementary mechanisms: NR2F1 re-activates developmental chromatin-remodeling and cytoskeletal programs, while NR2F6 operates via a conserved corepressor domain to impose broad translational repression, bind distal enhancers, and reorganize chromatin into new topologically associating domains that spatially cluster growth-associated genes with their regulatory elements.

Transcription factors are potent levers for neural repair, but systematic pipelines to uncover factors that unlock adult corticospinal regeneration are lacking. By intersecting developmental RNA-seq with ATAC-seq footprints, we pinpointed two nuclear-receptor transcription factors—NR2F1 and NR2F6, neither previously linked to CNS axon growth—as top candidates. Forced expression of either factor doubled neurite length in culture, and each proved highly effective in vivo: after unilateral pyramidotomy they drove robust midline sprouting, while after complete thoracic crush they supported long-tract CST regeneration that restored hip lift, partial swing trajectories and grip strength. Multi-omics dissection revealed complementary mechanisms: NR2F1 re-engaged chromatin-remodelling and cytoskeletal networks, whereas NR2F6, via a conserved corepressor domain, imposed a broad translational down-shift, bound predominantly to distal enhancers and re-packaged chromatin into new topologically associating domains that cluster growth genes with freshly activated regulatory hubs. These discoveries establish NR2F1 and NR2F6 as novel pro-regenerative TFs, demonstrate their potency across lesion types, and expose repression-driven translational control and enhancer–TAD reconfiguration as previously unrecognised axes of CNS repair.