Cervical spondylotic myelopathy (CSM) is a progressive disorder causing irreversible neurological damage, for which no effective non-surgical treatment modality exists. As chronic ischemia is a hallmark of pathology that may be amenable to pharmacological treatment, we hypothesized that aspirin could attenuate neurological decline. The twy (tiptoe) mouse hyperostosis model of chronic cervical cord compression was subject to daily intake of 25 mg / kg / day aspirin via drinking water from 4-weeks maturity onwards, equivalent to 100 mg / day in humans. Canal occupancy approached 40% by 3 months maturity but was unaffected by aspirin treatment. Aspirin significantly improved neurological measures as evidenced by prolonging balance (seconds, s) upon rotarod testing (39.12 ± 19.89s vs. 8.38 ± 6.46 vs, p = 0.011) and increasing forelimb grip strength (grams, g per gram body weight) at 3-months (0.54 ± 0.06 g/g, vs. 0.33 ± 0.06, p < 0.001) compared to untreated controls. This coincided with increased vessel volume

(VV) of the cervical spinal cord visualized by micro- CT imaging at 3-months in aspirin-treated animals compared to controls (6.41 ± 2.27% vs. 1.50 ± 0.65% VV/total volume, p = 0.002). Single-cell RNA sequencing identified microglia as a key responsive cell type, whilst lipidomic profiling indicated upregulation of the specialized pro-resolving mediator (SPM) lipoxin A4 (LXA₄) within the cervical cord. Moreover, the therapeutic response to aspirin was attenuated by Boc-2 which antagonizes LXA4 receptor binding; expression of the cytotoxic NLRP3 inflammasome was elevated in BV2 microglia culture with aspirin and Boc-2, whilst drug co-administration in twy mice reduced rotarod and grip strength to that of untreated controls. Our results provide compelling preclinical evidence supporting aspirin as a novel pharmacological avenue to treat DCM.