• Yan Yang, Wei Sun, Fan Yang, Ting Liang, Chun-Li Li, Yan Wang, Xiao-Liang Wang, Rui-Rui Wang, Shuang-Chan Wu, and Jun Chen.
• Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038 Shaanxi Province, PR China.
• Neuroscience. 2025 Feb 3.

AbstractPrediabetic neuropathic pain has been classified as peripheral neuropathic pain associated with polyneuropathy caused by impaired glucose tolerance or impaired fasting glucose, which is a preclinical stage and might develop type 2 diabetes mellitus. Our previous research highlighted that prediabetes is accompanied by dramatic bilateral mechanical hyperalgesia following high energy diet (HED) which results in myelin and axonal degenerations along somatosensory system. However, the pathogenic mechanisms underlying prediabetic neuropathic pain remain unclear. The nuclear sirtuin 6 (SIRT6) is a crucial deacetylase in the regulation of multiple cellular biological processes, such as DNA repair, genome stability, inflammation and metabolic homeostasis. In current study we show that the expressions of SIRT6 were significantly decreased, while its downstream NF-κB and proinflammatory mediator IL-6 and IL-1β were significantly increased in both dorsal root ganglia (DRG) and spinal dorsal horn of rats with prediabetic neuropathic pain induced by HED. Moreover, siRNA-SIRT6 treatment induced a significant reduction in bilateral paw withdrawal mechanical thresholds, indicating that SIRT6 down-regulation contributed to prediabetic neuropathic pain induced by HED. Furthermore, it was also found that SIRT6 reduction induced the activation of HMGB1 via disinhibition of NF-κB in both DRG and spinal dorsal horn of prediabetic rats. In conclusion, prediabetic neuropathic pain is caused by SIRT6 reduction through upregulating HMGB1-RAGE signaling at both peripheral and spinal levels.Copyright © 2025. Published by Elsevier Inc.

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