CITED2 is a druggable epigenetic switch coupling neuronal maturation to regenerative decline.

Neuronal maturation involves a tightly regulated cessation of growth and acquisition of polarity, ultimately leading to synapse formation. While essential for circuit stability, maturation marks the loss of regenerative capacity after central nervous system (CNS) injury. The molecular programs coupling maturation to regenerative decline remain incompletely understood. Here, we show that the transcriptional and epigenetic signatures enabling axon growth in dorsal root ganglion (DRG) neurons are lost as they transition from immature, non-polarized cells to mature, pseudo-unipolar neurons. We identify the transcriptional co-regulator CITED2 as a key epigenetic switch, active in immature and regenerating DRG neurons but silent after non-regenerative spinal cord injury (SCI). Cited2 overexpression reactivates growth programs, enhancing regeneration in vivo after SCI. Mechanistically, CITED2 reinstates developmental epigenetic and transcriptional profiles, decoupling maturation from regenerative failure. Pharmacogenomic screening identified CITED2 as a target of the clinically approved HDAC inhibitor Panobinostat, which promoted axonal growth, sprouting, and functional recovery post-injury. These findings position CITED2 as a key regulator of sensory neuron plasticity and a novel therapeutic target for CNS repair.