Targeting RARβ With a Stable Retinoic Acid Mimic Promotes Neurite Outgrowth, Neurogenesis, and Behavioral Recovery
Sanyal, K.; Haque, S. R.; Pendharkar, R.; Chermakani, P.; Kumaran, M.; Acharya, P.; Maity, D.; Venkatesh, I.
Show abstract
Injury to the adult central nervous system triggers minimal axonal regeneration, partly due to the limited activation of intrinsic growth programs. Retinoic acid (RA) signaling has been shown to promote modest regenerative responses, but its clinical utility is restricted by poor biochemical stability and short-lived receptor engagement. Here, we report small molecule based synthetic RA mimic, DM04, that stabilizes RA-like signaling and enhances regenerative outcomes. DM04 promoted neurite outgrowth in primary neurons, upregulated canonical RA-responsive genes, and supported neural induction from human iPSCs. In a murine spinal injury model, DM04 treatment improved motor recovery. Transcriptomic analysis revealed shared target gene activation between RA and DM04, along with unique enrichment of extracellular matrix remodeling pathways. These findings establish DM04 as a chemically stable modulator of RA signaling with dual efficacy in injury and developmental contexts, highlighting its promise as a candidate for regenerative therapeutics.
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