PRMT6 inhibition or deficiency attenuates diabetic neuropathic pain in male mice and is associated with reduced spinal neuroinflammation, microgliosis, and altered p53-p21 signaling.

Diabetic neuropathic pain (DNP) is a major contributor to chronic pain in adults, yet effective targeted therapies are still lacking, underscoring the need to elucidate its underlying mechanisms. Microglial proliferation and activation are key drivers of central sensitization and pain hypersensitivity. In a type 2 diabetes mouse model, protein arginine methyltransferase 6 (PRMT6) was markedly upregulated in spinal dorsal horn microglia in male mice, and high-glucose stimulation similarly increased PRMT6 expression in BV-2 cells, accompanied by enhanced proliferation and inflammatory activation. Genetic deletion of Prmt6 or pharmacological inhibition with EPZ020411 alleviated pain hypersensitivity and reduced spinal microgliosis and inflammation in male mice. Transcriptomic analysis revealed enrichment in cell proliferation-related processes and the p53 signaling pathway. In BV-2 cells, PRMT6 knockdown induced G0/G1 arrest and attenuated high-glucose-induced proliferation and inflammatory activation, whereas PRMT6 overexpression exerted opposite effects. Mechanistically, PRMT6 methylated p53 and decreased its transcriptional activity, leading to reduced p21 mRNA expression and enhanced cell-cycle progression. In contrast, in female DNP mice, spinal microgliosis was limited, PRMT6 expression remained unchanged, and Prmt6 deficiency did not significantly alter spinal microglial density, inflammatory markers, or nociceptive hypersensitivity. Collectively, our results uncover a previously unrecognized PRMT6-p53-p21 regulatory axis that may contribute to microglial proliferation and neuroinflammation under hyperglycemic conditions in male mice, highlighting PRMT6 as a potential therapeutic target for microglia-associated DNP.