Axonal transcriptome remodeling during PGE2 induced sensitization identifies Tnfrsf12a/FN14 as a regulator of sensory neuron excitability

Axonal mRNA translation is a key regulator of neuronal plasticity, yet its contribution to inflammatory pain remains poorly defined. Here, we combine compartmentalized dorsal root ganglion (DRG) neuron cultures with RNA sequencing to map axonal and somatic transcriptomes and their remodeling following prostaglandin E 2 (PGE 2 )-induced sensitization. We identify a conserved axonal transcriptome across embryonic and adult neurons, enriched for ribosomal and mitochondrial functions, supporting sustained local translation and metabolic activity. PGE 2 triggers compartment-specific transcriptomic reprogramming, with axons showing enrichment of inflammatory and pain-related pathways, while somatic responses favor translational processes. Functionally, axonal PGE 2 exposure enhances neuronal excitability and drives retrograde sensitization. Integrative analyses identify Tnfrsf12a (Fn14) as an axonally localized, PGE 2 -responsive transcript whose local knockdown reduces excitability and attenuates sensitization. These findings establish axonal transcriptome dynamics as key drivers of peripheral sensitization and highlight axonally localized mRNAs as spatially precise therapeutic targets for inflammatory pain.