Sox9 regulation of hexokinase 1 controls neuroinflammatory astrocyte subtypes in a rat model of neuropathic pain.

Neuropathic pain, caused by nerve damage, lacks effective treatments. Astrocytes drive chronic neuroinflammation in the dorsal horn, but directly targeting them is challenging due to their heterogeneity and beneficial roles. The regulation of deleterious astrocyte subset emergence in pain is also unknown. Here, we identify distinct astrocyte clusters and elucidate mechanisms by which metabolic regulation of neuroinflammatory astrocyte subsets during pain pathogenesis. We show that the astrocyte specifier Sox9 transcriptionally regulates hexokinase 1 (Hk1), the enzyme that catalyzes the rate-limiting first step of glycolysis. Nerve damage induces abnormal Sox9 phosphorylation, triggering aberrant Hk1 activation for high-rate astrocytic glycolysis. Moreover, the excessive lactate production from heightened glycolysis remodels histones of gene promoters via lactylation, H3K9la, promoting transcriptional modules of pro-inflammatory and neurotoxic genes, which induce pathogenic astrocyte properties while reducing beneficial populations, ultimately causing NeP. Importantly, targeted modulation of the Sox9-Hk1-H3K9la axis specifically dampens neuroinflammatory astrocyte subsets, promoting long-lasting pain relief. Collectively, our findings unveil an important immunometabolic mechanism and identify potential targets for neuropathic pain treatment.