Ononin modulates SIRT2-mediated glycolysis and inflammation in LPS-activated microglia via PKM2 deacetylation.

Background: Inhibition of inflammation and glycolysis of microglia contributes to neuropathic pain treatment. Ononin, a compound isolated from various plants, has been found to have various anti-inflammatory and anti-tumor effects.

Objective: To investigate the therapeutic potential and mechanism of Ononin on microglial activation.

Methods: BV2 microglial cells were treated with LPS to mimic microenvironment of neuropathic pain in vitro, and gene expression was analyzed by qPCR array analysis after Ononin treatment. The effects of Ononin and SIRT2 gene on inflammation and glycolysis were then investigated. PKM2 acetylation sites were predicted using the GPS-PAL database. The interaction between PKM2 and SIRT2 protein was also studied.

Results: Ononin at 40 μM significantly inhibited inflammation and glycolysis in LPS-treated BV2 microglial cells, and this was related to the upregulation of SIRT2 levels. Inhibition of SIRT2 weakened the regulatory effects of Ononin, and induced PKM2 acetylation to enhance glycolysis in BV2 cells. SIRT2 exerts deacetylation modification at K207 site of PKM2 protein to reduce the stability of PKM2 protein.

Conclusions: SIRT2-mediated metabolic reprogramming and inflammation are critical for neuropathic pain, and Ononin shows therapeutic potential by modulating SIRT2 to suppress PKM2 protein stability in the deacetylation way, suggesting it as a promising treatment option.