Spinal microglia mediate chronic itch by promoting ferroptosis

Chronic itch, affecting 8-10% of the global population, is a debilitating condition linked to dermatoses, systemic diseases, and neurological disorders, with limited therapeutic efficacy due to unclear central mechanisms. Spinal microglia, central nervous system-resident immune cells, regulate neuroinflammation and synaptic plasticity in chronic pain and neurodegeneration, but their role in chronic itch remains unknown. This study investigated the role of spinal microglia in chronic itch. Using an allergic contact dermatitis (ACD) mouse chronic itch model, we found robust microglial activation, accompanied by c-Fos-positive neuronal activation, in the spinal dorsal horn of a chronic itch model. Pharmacological inhibition (minocycline) or genetic ablation of microglia significantly reduced mechanical itch hypersensitivity and spontaneous scratching, alongside decreased microglial/neuronal activation. Morphological and molecular analyses revealed downregulated antioxidants (glutathione peroxidase 4 [GPX4], superoxide dismutase [SOD], glutathione [GSH],) and upregulated lipid peroxidation (malondialdehyde [MDA], acyl-CoA synthetase long-chain family member 4 [ACSL4]) in the spinal cord, indicating ferroptosis. Intrathecal liproxstatin-1 (ferroptosis inhibitor) alleviated itch behaviors and restored GPX4, SOD, GSH and MDA level, without affecting microglial activation. Our findings demonstrate that spinal microglia promote chronic itch by triggering ferroptosis in spinal dorsal horn. These findings provide the first evidence of microglia-ferroptosis crosstalk in chronic itch, providing a mechanistic basis for targeting glial activity or ferroptosis to develop novel therapies.