A purinergic glia-neuron circuit underlying bortezomib neurotoxicity.
Bortezomib-induced peripheral neuropathy (BIPN) is a major dose-limiting toxicity of proteasome inhibitor therapy, yet how bortezomib converts proteotoxic stress into persistent peripheral pain remains poorly defined. Here, we identify extracellular ATP as a cell-type-organized instructive signal, rather than a passive injury marker, that drives BIPN through a dorsal root ganglion glia-neuron circuit. Integrating clinical phenotyping, single-cell transcriptomics, in vivo ATP and calcium imaging, spatial histology, cell-type-restricted gene silencing and pharmacological perturbation, we found that bortezomib selectively induces a P2RX7-high reactive state in classical perisomatic satellite glial cell Cluster1. P2RX7 activation promotes PANX1 pore opening and burst ATP release within the perisomatic microenvironment. This glial ATP signal is decoded by adjacent P2RX3-enriched C6 non-peptidergic sensory neurons, triggering neuronal calcium hyperactivity and mechanical and cold hypersensitivity. Genetic or pharmacological blockade of P2RX7, PANX1 or P2RX3 interrupted this emitter-messenger-decoder axis and alleviated pain. Low-dose multi-node inhibition produced synergistic analgesia, while probenecid-based regimens preserved or enhanced bortezomib antimyeloma efficacy. In patients, peripheral classical monocyte ATP release mirrored purinergic-axis activation, correlated with neuropathy severity and chronicity, and outperformed serum ATP for stratification. These findings define BIPN as a targetable purinergic glia-neuron circuit disorder and nominate ATP-release competence as a functional liquid-biopsy biomarker for mechanism-guided neuroprotection.