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Alyref Deficiency Exacerbates Chronic Inflammatory Pain by Impairing m5C-Dependent Nuclear Export of Ccn3 mRNA

ABSTRACT: The 5-methylcytosine (m⁵C) RNA modification regulates multiple aspects of RNA metabolism; however, its contribution to pathological pain remains poorly understood. Here, we investigated the role of the m⁵C reader Alyref in a mouse model of complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain. We observed a marked and sustained upregulation of Alyref in nociceptive neurons of the dorsal root ganglion (DRG) following CFA administration. Conditional deletion of Alyref in NaV1.8⁺ nociceptive neurons significantly exacerbated thermal and cold hypersensitivity, mechanical allodynia, and hyperalgesia. These behavioral abnormalities were accompanied by pronounced activation of microglia and astrocytes in the spinal dorsal horn, along with elevated expression of proinflammatory mediators, indicating enhanced neuroinflammation and central sensitization. Mechanistically, Alyref directly binds to m⁵C-modified Ccn3 mRNA and promotes its nuclear export, thereby maintaining cytoplasmic Ccn3 expression in DRG neurons. Loss of Alyref impaired Ccn3 mRNA export, reduced Ccn3 expression, and was associated with increased level of MMP-9, a key mediator of neuroinflammatory pain signaling. Collectively, these findings identify Alyref as a protective regulator in chronic inflammatory pain by restraining neuroinflammation and limiting the emergence of neuropathic pain-like features. Our study highlights a previously unrecognized role of m⁵C-dependent RNA regulation in nociceptive sensitization and suggests Alyref as a potential therapeutic target for pathological pain.

ORGANISM(S): Mus musculus

PROVIDER: GSE321975 | GEO | 2026/07/08

REPOSITORIES: GEO

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Project description:Background: The pathogenesis of neuropathic pain and the reasons for the prolonged unhealing are still unknown. Increasing evidence suggests that oestrogen sex differences play a role in pain sensitivity, but few studies focused on the role of oestrogen receptor which maybe an important molecular component contributing to peripheral pain transduction. We aimed to investigate the impact of ooestrogen receptors in nociceptive neuronal response in the dorsal root ganglion (DRG) and spinal dorsal horn using a spared nerve injury (SNI) rat model of chronic pain. Methods: We used a class of oestrogen receptors antagonists and agonists intrathecal (i.t.) administrated to male rats with SNI or normal rats to identify the main receptor. Moreover, we applied genes identified through genomic metabolic analysis to determine the key metabolism point and elucidate potential mechanisms mediating continuous neuronal sensitisation and neuroinflammation responses in neuropathic pain. The excitability of DRG neurons was detected using the patch clamp technique. Primary culture was used to extract microglia and DRG neurons, and siRNA transfection was used to silence receptor protein expression. Immunofluorescence, Western blotting, qPCR and behavioral testing were used to assess the expressions, cellular distributions, and actions of main receptor and its related signaling molecules. Results: Increasing the expression and function of G protein-coupled oestrogen receptor (GPER), but not oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ), in the DRG neuron and microglia, but not the dorsal spinal cord, contributed to SNI-induced neuronal sensitisation. Inhibiting GPER expression in the DRG alleviated SNI-induced pain behaviours and neuroinflammation by downregulating iNOS, IL-1β and IL-6 expression as well as restoring GABAα2 expression simultaneously. Additionally, the positive interaction between GPER and β-alanine, β-alanine accumulation enhances pain sensation and promotes chronic pain development. Conclusion: GPER activation in the DRG causes a positive interaction of β-alanine with iNOS, IL-1β and IL-6 expression and represses GABAα2 involved in post-SNI neuropathic pain development. Blocking GPER and eliminating β-alanine in the DRG neuron and microglia may prevent neuropathic pain development.

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Alyref Deficiency Exacerbates Chronic Inflammatory Pain by Impairing m5C-Dependent Nuclear Export of Ccn3 mRNA

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