Targeting sex-specific DRG inflammation and neurofibrosis to prevent Bortezomib-induced neuropathy

Peripheral neuropathy is a common and often debilitating side effect of the chemotherapeutic agent bortezomib (BTZ), yet its mechanisms remain incompletely understood. To investigate the pathogenesis of BTZ-induced peripheral neuropathy (BIPN), we developed a mouse model that mimics the clinical route and prolonged duration of BTZ administration. In this model, male mice exhibited significantly greater sensorimotor deficits and axonal loss than females. Analysis of clinical data corroborated these findings, revealing that men with BIPN more frequently demonstrated absent sural nerve amplitudes and diminished distal sensation compared to women. To explore sex-specific responses to BTZ, we examined the dorsal root ganglia (DRG) microenvironment and found that BTZ primarily impacts non-neuronal cells. Among these, satellite glial cells (SGCs) exhibited the most pronounced baseline sex differences in gene expression and mounted the strongest transcriptional response to BTZ. In females with BIPN, SGCs upregulated genes involved in lipid metabolism, whereas in males, they strongly induced genes associated with extracellular matrix (ECM) remodeling, resulting in substantial collagen deposition in the DRGs. Because excessive ECM accumulation often reflects chronic immune activation, we investigated immune cell dynamics and observed a marked expansion of immune populations-particularly macrophages-in males. Depleting macrophages with anti-CSF1R in male mice attenuated BTZ-induced SGC reactivity, restored ECM homeostasis, preserved axons, and improved sensorimotor function. These findings implicate neuroinflammation and ECM dysregulation within the DRG as central mechanisms driving sex-specific vulnerability to BIPN and position the DRG microenvironment as a promising target for therapeutic intervention.