Circular RNA circNrip1 Interacts with SYNCRIP to Promote Neuropathic Pain by Stabilizing Tlr2 mRNA in Primary Sensory Neurons

ABSTRACT Nerve injury–induced gene dysregulation in the dorsal root ganglion (DRG) is considered a key molecular basis for neuropathic pain genesis. Circular RNA is emerging as a critical regulator of gene expression. Here, we reported a novel circular RNA circNrip1 formed by back‐splicing from exon 3 to exon 2 of the Nrip1 pre‐RNA. Peripheral nerve injury upregulates circNrip1 , but not Nrip1 mRNA, in injured DRG neurons, at least in part due to increased binding of the RNA‐binding protein FUS to Nrip1 pre‐RNA, thereby promoting circNrip1 formation. Blocking this upregulation attenuates nerve injury–induced increases in toll‐like receptor 2 ( Tlr2 ) mRNA and TLR2 protein levels in injured DRG, as well as nerve injury–induced nociceptive hypersensitivity. Conversely, mimicking this upregulation elevates DRG Tlr2 mRNA and TLR2 protein expression and produces neuropathic pain‐like symptoms in naïve mice. Mechanistically, upregulated circNrip1 enhances its binding to the 3′‐ untranslated region (UTR) of Tlr2 mRNA and to the RNA‐binding protein SYNCRIP, thereby recruiting more SYNCRIP to the Tlr2 mRNA 3′‐UTR and stabilizing Tlr2 mRNA in injured DRG neurons. Thus, circNrip1 contributes to neuropathic pain by promoting SYNCRIP‐triggered stabilization of TLR2 in DRG neurons and represents a promising therapeutic target for intervention.