Cornuside alleviates microglia-mediated neuroinflammation to ameliorate chronic neuropathic pain-induced cognitive impairment via the Nrf2/Sirt3 signaling pathway.

Cognitive impairment induced by chronic neuropathic pain (CNP-CI) is a severe complication that markedly compromises patients' quality of life, functional independence, and overall disease burden. However, current pain management strategies demonstrate limited efficacy in preventing or reversing this cognitive decline. Cornuside, an active flavonoid glycoside isolated from the traditional Chinese herb Cornus officinalis, demonstrates potent anti-inflammatory and antioxidative stress properties, however, its therapeutic potential for the treatment of neuropathic pain remains to be elucidated. In this study, we demonstrated that cornuside effectively alleviated microglial inflammation and improved cognitive impairment induced by chronic neuropathic pain. Mechanistically, cornuside ameliorated microglia-mediated neuroinflammation through activation of the Nrf2/Sirt3 signaling pathway and enhancement of mitophagy. Notably, pharmacological inhibition of Sirt3 markedly counteracted the therapeutic effects of cornuside on microglial inflammation and CNP-CI. Our findings provide new insights into the pharmacological mechanisms of cornuside and suggest its potential as a viable therapeutic approach for CNP-CI.