Cancer-associated metabolic alterations facilitated by astrocyte glycogenolysis mediate neuropathic pain chronification

Metabolic signaling in astrocytes has been implicated in a range of neurophysiological disorders. Likewise, pain chronification, which is defined as the transition from an acute pain state to a persistent one in response to repeated or intense nociceptive stimuli, involves crucial contributions from astrocytes. Although lactate transport by anterior cingulate cortex (ACC) astrocytes has been shown to influence pain chronification, the specific metabolic pathways and upstream signaling events remain poorly understood. In this study, we identified glycogenolysis in ACC astrocytes as a central signaling mechanism controlling pain chronification. Inhibition of glycogenolysis suppressed pain‐related behaviors and normalized neuronal hyperactivity. To extend the effects of glycogenolysis to broader metabolic dynamics, we conducted integrated transcriptomic and metabolomic analyses as chronic pain progressed. Interestingly, those analyses revealed that chronic pain was accompanied by a shift toward cancer‐associated metabolic programs in the ACC, and that shift was driven by astrocytic glycogenolysis. Taken together, our findings demonstrate that pain chronification is mediated by astrocytic glycogenolysis, which induces a cancer-associated metabolic pathway. Therefore, alterations in astrocytic glycogen metabolism could be key signals for cancer‐associated metabolic reprogramming. These findings offer novel insights into astrocyte-driven oncogenic metabolic regulation in neuropathic pathology.