Neonatal-Inspired Reprogramming of Microglial Pan-Programmed Cell Death Enhances Regeneration in Adult Spinal Cord Injury.

In adult mammals, programmed cell death (PCD) facilitates tissue remodeling and regeneration in spinal cord injury (SCI), but excessive activation impedes SCI repair. However, no comprehensive pan-PCD atlas exists that encompasses diverse cell death patterns to fully elucidate PCD in adult SCI and develop strategies for modulating the excessive PCD response. Here, we identified neonatal mice with balanced PCD post-SCI as an ideal model for adult SCI. Accordingly, we developed "Thanatoset", an SCI-specific gene panel to map tissue and cellular pan-PCD dynamics across neonatal and adult mice. Microglia were identified as pivotal mediators of pan-PCD, showing greater vulnerability in adults than in neonates. According to computational drug screening, withaferin A can revert microglial pan-PCD in adults to a neonatal-like regenerative state. Histological, functional, and molecular analyses corroborated that withaferin A enhances SCI recovery in adults by modulating microglial pan-PCD. These findings highlight the therapeutic potential of the pan-PCD framework for developing strategies to restore regeneration and improve SCI outcomes.