Astrocytic Phenotypic Switching in Posterior Piriform Cortex Orchestrates Bone Cancer Pain–Depression Comorbidity via Purinergic–Noradrenergic Signaling

ABSTRACT Bone cancer pain occurs in up to 70% of patients with skeletal metastases and is accompanied by depression, severely diminishing quality of life. Current pharmacological strategies provide only partial relief, and the neurobiological mechanisms linking nociceptive and affective processing remain poorly defined. Herein, in a mouse model of Lewis lung carcinoma, we identify a previously uncharacterized astrocyte–neuron signaling axis in the posterior piriform cortex that underlies bone cancer pain with comorbid depression. Through metabolomic, proteomic, and fiber photometry approaches, we show that astrocytic phenotypic transition from the neuroprotective A2 to the neurotoxic A1 state triggers metabolic reprogramming, downregulates ATP/adenosine/adenosine A2A receptor signaling, and upregulates the norepinephrine transporter, impairing noradrenergic transmission. Interventions targeting astrocyte phenotypes, including minocycline and Lcn2 knockdown, normalized the posterior piriform cortex neurochemistry and alleviated both nociceptive and affective symptoms. These findings define a mechanistic framework in which astrocytic dysfunction orchestrates pain and depression, and highlight astrocyte‐directed strategies for treating cancer pain–depression comorbidity.