Spinal CircKcnk9 Regulates Chronic Visceral Hypersensitivity of Irritable Bowel Syndrome

•Spinal circKcnk9 was involved in visceral hypersensitivity of IBS-like rats.•Spinal high circKcnk9 facilitated STAT3 expression by inhibiting miR-124-3p silencing effect in Irritable bowel syndrome (IBS).•The study reveals a novel epigenetic mechanism of visceral hypersensitivity in IBS.•ShcircKcnk9 could be used as a candidate for the treatment of chronic functional visceral pain. Dysregulation of circular RNAs (circRNAs) has been reported to be functionally associated with chronic pain, but it is unknown whether and how circRNAs participate in visceral hypersensitivity. The expression of circKcnk9 was increased in spinal neurons of irritable bowel syndrome (IBS)-like rats. ShcircKcnk9 attenuated visceral hypersensitivity and inhibited c-Fos expression in IBS-like rats, whereas overexpression of spinal circKcnk9 induced visceral hypersensitivity and increased c-Fos expression in control rats. Furthermore, circKcnk9 was found to act as a miR-124-3p sponge. MiR-124-3p antagomir restored pain responses downregulated by shcircKcnk9 in IBS-like rats. Finally, the signal transducer and activator of transcription 3 (STAT3), validated as a target of miR-124-3p, could play a critical role in visceral hypersensitivity by regulating NSF/GluR2. Spinal circKcnk9 functions as a miR-124-3p sponge to promote visceral hypersensitivity by regulating the STAT3/NSF/GluR2 pathway. This pathway might provide a novel epigenetic mechanism of visceral hypersensitivity and a potential circRNA therapeutic target for IBS. [Display omitted] Spinal circKcnk9 functions as a miR-124-3p sponge to promote visceral hypersensitivity by regulating the STAT3/NSF/GluR2 pathway.