FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain via m 6 A-dependent stabilization of 5-HT3A mRNA in sensory neurons

• DOI: 10.1073/pnas.2312861121
• Publication Date: 2024-01-29T20:00:21Z
• Authors: Zitong Huang; Yuan Zhang; Shoupeng Wang; Renfei Qi; Yu Tao; Yufang Sun; Dongsheng Jiang; Xinghong Jiang; Jin Tao
• Keywords: Nerve Injury; Demethylase; Trigeminal ganglion

The N6-methyladenosine (m 6 A) modification of RNA is an emerging epigenetic regulatory mechanism that has been shown to participate in various pathophysiological processes. However, its involvement modulating neuropathic pain still poorly understood. In this study, we elucidate a functional role the m A demethylase alkylation repair homolog 5 (ALKBH5) trigeminal-mediated pain. Peripheral nerve injury selectively upregulated expression level ALKBH5 injured trigeminal ganglion (TG) rats. Blocking upregulation TGs alleviated pain, while mimicking intact TG neurons sufficiently induced pain-related behaviors. Mechanistically, histone deacetylase 11 downregulation by increases H3 lysine 27 acetylation (H3K27ac), facilitating binding transcription factor forkhead box protein D3 (FOXD3) Alkbh5 promoter and promoting transcription. increased erases sites Htr3a messenger (mRNA), resulting inability YT521-B homology domain 2 (YTHDF2) bind mRNA, thus causing increase 5-HT3A 5-HT3 channel currents. Conversely, blocking destabilizes injury–induced reverses mechanical allodynia, effect can be blocked knockdown. Together, FOXD3-mediated transactivation promotes through A-dependent stabilization mRNA neurons. This mechanistic understanding may advance discovery new therapeutic targets for management.