Microglial macrophage-derived ds-HMGB1 in DRG orchestrates neuropathic pain through immune-neural signaling

Neuroimmune crosstalk in the dorsal root ganglion (DRG) plays a pivotal role in neuropathic pain driven by chemotherapy-induced peripheral neuropathy (CIPN). Here, we report that the pro-inflammatory disulfide isoform of high-mobility group box 1 (ds-HMGB1) is a key mediator of oxaliplatin-induced neuropathic pain, with DRG microglia-like tissue-resident macrophages (M-TRMφs) as its primary reservoir. Mechanistically, protein disulfide isomerase A3 (PDIA3) catalyzes HMGB1 oxidation to ds-HMGB1 via Cys23-Cys45 bond formation, while gasdermin D (GSDMD)-mediated pyroptosis drives its release. Released ds-HMGB1 engages Toll-like receptor 4 (TLR4) on C2-subtype sensory neurons, triggering nuclear factor κB (NF-κB)-dependent upregulation of transient receptor potential vanilloid 1 (TRPV1) and amplifying mechanical allodynia. PDIA3, GSDMD, or ds-HMGB1 inhibition alleviates pain without compromising oxaliplatin's anti-tumor efficacy. Serum ds-HMGB1 correlates with pain severity in oxaliplatin-treated patients. M-TRMφ-derived ds-HMGB1 orchestrates neuropathic pain through pyroptotic release and TLR4/TRPV1 signaling in a redox-regulated macrophage-neuron axis in the DRG. ds-HMGB1 emerges as a potential biomarker and therapeutic target in CIPN.