Activation of the NR3C1–STAT3–SLC6A2 signaling axis by a cyanidin-3-O-glucoside–enriched anthocyanin preparation attenuates neuroinflammation and pain hypersensitivity in intervertebral disc degeneration

IVDD is a major global health burden and a leading cause of chronic low back pain, yet disease-modifying therapies remain limited. Anthocyanins are natural anti-inflammatory compounds with potential neuroprotective activity, but their roles in IVDD-related neuroinflammation and nociceptive sensitization are unclear. Anthocyanins used in this study were a commercially standardized preparation (≥ 98% purity), in which cyanidin-3-O-glucoside (C3G) constituted the predominant component as confirmed by LC–MS analysis. IVDD was established by needle puncture in rats and conditional Cre–loxP mice. Mechanical and thermal pain behaviors were assessed, and disc pathology was evaluated by imaging and histological/biochemical analyses. IL-1β–stimulated NP cultures and NP–DRG co-cultures were used to model neuron–disc interactions. Mechanistic studies combined pharmacological modulation and genetic targeting of NR3C1/STAT3 with assays of NR3C1 nuclear translocation, NR3C1–STAT3 interaction, and STAT3 binding to the SLC6A2 promoter. Cyanidin-3-O-glucoside (C3G)–enriched anthocyanin preparation reduced IVDD-associated neuroinflammation and pain hypersensitivity, improved disc degeneration, and decreased NP apoptosis and inflammatory mediator release. Mechanistically, anthocyanins activated the NR3C1–STAT3–SLC6A2 axis, enhancing NR3C1 nuclear localization, promoting NR3C1–STAT3 coupling, and restoring SLC6A2 expression in sensory neurons. Disrupting NR3C1 or STAT3 weakened these protective and antinociceptive effects. C3G-enriched anthocyanins alleviate IVDD-related neuroinflammation and pain primarily via the NR3C1–STAT3–SLC6A2 signaling axis.