Targeting the catalytic and ZnF-UBP domains of HDAC6 differentially controls NLRP3 inflammasome priming and assembly in paclitaxel-induced peripheral neuropathy

Paclitaxel-induced peripheral neuropathy (PIPN) is a dose-limiting complication of cancer chemotherapy driven by macrophage-mediated NLRP3 inflammasome activation. While suppressing TLR-NF-κB-dependent priming can limit neuroinflammation by reducing both NLRP3 induction and downstream inflammasome activation, such upstream intervention may also affect broader immune transcriptional programs in vulnerable oncology patients. Here, we identify a structural division of labor within histone deacetylase 6 (HDAC6) that pharmacologically uncouples the priming and assembly steps of NLRP3 activation. In a murine PIPN model, we demonstrate that paclitaxel directly primes macrophages. Complementary ND7/23-BMDM experiments support a model in which ATP released from paclitaxel-stressed neuronal cells provides a second signal for inflammasome assembly. By integrating domain-selective pharmacology with genetic knockdown-rescue using catalytically inactive and ZnF-UBP-deletion mutants, we reveal that the catalytic domain of HDAC6 governs upstream TLR4-NF-κB-dependent priming. In contrast, the non-catalytic ZnF-UBP domain is required for downstream HDAC6-NLRP3-ASC complexation and ASC speck assembly, ultimately driving caspase-1 activation, GSDMD cleavage, and IL-1β release. In vivo, targeting the ZnF-UBP domain with CP31 effectively alleviated paclitaxel-evoked pain hypersensitivity and dorsal root ganglion (DRG) neuroinflammation without altering canonical α-tubulin acetylation. By reframing HDAC6 into domain-separable intervention points, we provide a pathway-restricted therapeutic strategy for PIPN that precisely disarms downstream pathological inflammasome assembly while largely preserving the measured upstream priming responses.