Single-cell analyses identify persistent neuroimmune remodeling and prioritize SPP1 and LGALS3 in neuropathic pain

Introduction Persistent neuropathic pain involves lasting sensory and immune changes. We examined which expression programs persist across injury settings and whether prioritized genes are associated with pain severity. Methods We analyzed five public single-cell or single-nucleus transcriptomic resources and two independent bulk RNA-sequencing resources, then examined tissue expression and behavior in spared nerve injury experiments. Results Microglial expression showed a distinct early response and persistent glial-program activity. The glial signature remained elevated at day 14 and month 5 after exclusion of Spp1 and Lgals3 (false-discovery-adjusted q=0.0473 and 0.00128). Independent bulk data supported neuronal injury-related and glial programs, although candidate-gene effects varied across populations and stages. Spp1 and Lgals3 retained high priority in ranking sensitivity analyses, and their dorsal root ganglion expression correlated with mechanical hypersensitivity after adjustment for collection endpoint. Post-injury Lumogallion treatment increased the day-14 paw-withdrawal threshold (treated/vehicle geometric-mean ratio 4.08, 95% confidence interval 2.53–6.55) and reduced selected dorsal root ganglion and spinal transcripts. Structural modeling proposed an LGALS3–Lumogallion interaction for experimental testing. Discussion These findings link persistent neuroimmune expression programs to tissue-level Spp1 and Lgals3 associations and show partial behavioral improvement with Lumogallion. Direct target-engagement studies are planned to determine whether LGALS3 contributes to this response.