Hyperglycemia-responsive circRNA drives diabetic neuropathic pain by competing for PUM2 binding and promoting proNT3/CCL2 in DRG neurons

Diabetic neuropathic pain (DNP), one of the most common and debilitating complications of diabetes mellitus (DM), remains poorly managed by conventional analgesics, highlighting the urgent need to explore its etiology-associated mechanisms. Here, we identified a novel conserved circular RNA, cRps6kb1, that is significantly upregulated in dorsal root ganglion (DRG) neurons across multiple mouse models of type 1 DM and type 2 DM, as well as in human donors with DNP. Blocking cRps6kb1 upregulation attenuated the increases in DRG neurotrophin-3 mRNA (Nt3), its encoded proneurotrophin-3 (proNT3), and downstream C-C chemokine ligand 2 (CCL2) expression, as well as the persistence of nociceptive hypersensitivity under the conditions of streptozotocin-induced type 1 DM or high-fat diet-fed type 2 DM. Conversely, mimicking cRps6kb1 upregulation increased DRG Nt3, proNT3, and CCL2 levels and produced DNP-like symptoms in naive mice. In addition, high glucose increased the expression of cRps6kb1 and Nt3 in cultured DRG neurons from mice and human donors. Mechanistically, upregulated cRps6kb1 competed with the Nt3 3'-untranslated region (3-UTR) for the translational repressor PUM2 binding, releasing PUM2 from the Nt3 3-UTR and enhancing Nt3 mRNA translation and stability. Thus, cRps6kb1 is a key contributor to DNP and represents a promising therapeutic target for its treatment.