Satellite glial GLRX3 drives ageing-biased neuropathic pain via HMGB1

Abstract Chronic neuropathic pain disproportionately affects older individuals, particularly in the context of persistent oxaliplatin-induced peripheral neuropathy (OIPN); however, the molecular mechanisms sustaining this ageing-biased chronicity remain elusive. In this study, we integrated age-stratified murine models and a multicentre longitudinal cohort of patients receiving oxaliplatin-based chemotherapy for colorectal cancer to investigate a glia-to-neuron redox circuit in the dorsal root ganglion. Using single-nucleus RNA sequencing and redox proteomics, we identified selective upregulation of the deglutathionylase glutaredoxin-3 (GLRX3) in satellite glial cells in aged mice during the chronic phase of OIPN. This upregulation leads to a pronounced loss of protein S-glutathionylation (PSSG) within the dorsal root ganglion, a pattern absent in young mice and during acute stages. Mechanistically, GLRX3, via its catalytic Cys148 residue, catalyses the deglutathionylation of high-mobility group box 1 (HMGB1) at the Cys106 site. This modification converts HMGB1 into a potent agonist for the toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex, triggering neuronal nuclear factor-κB signalling and the subsequent upregulation of transient receptor potential ankyrin 1 and vanilloid 2 channels in PACAP-positive (C1 subtype) peptidergic nociceptors, thereby sustaining long-term mechanical and cold hypersensitivity. Satellite glial cell-targeted knockdown of GLRX3 restored HMGB1 glutathionylation and reversed the pain phenotype specifically in aged mice. In the clinical cohort, advanced age was significantly associated with a higher incidence of chronic neuropathy. Longitudinal serum analysis revealed that systemic levels of PSSG and glutathionylated HMGB1 declined progressively and correlated inversely with pain duration, particularly among older individuals. Furthermore, oral γ-glutamylcysteine or pharmacologic TLR4 blockade (TAK-242) effectively alleviated refractory hypersensitivity in aged models. These findings define the satellite glial GLRX3-HMGB1-TLR4 redox axis as a critical driver of age-biased neuropathic pain. Circulating PSSG represents a novel age-stratified clinical biomarker, and targeting this redox-sensitive pathway offers a promising therapeutic strategy for geriatric and chemotherapy-related neuropathies.