CXCL10 activates STAT3 signaling to promote ferroptosis in the spinal dorsal horn during neuropathic pain.

Neuropathic pain (NP) remains a clinical challenge due to the limited efficacy and significant side effects of current treatments, highlighting the need for a deeper understanding of its pathogenesis. While dysfunction of GABAergic inhibitory neurons in the spinal dorsal horn is a known key driver of central sensitization, the mechanisms precipitating this neuronal injury remain obscure. In this study, using a spinal nerve ligation (SNL) model, we aimed to investigate whether the chemokine CXCL10 drives NP progression by promoting ferroptosis, a process that is associated with and ultimately leads to the loss of GABAergic neurons. We observed that mechanical hypersensitivity in post-SNL rats coincided with progressive spinal ferroptosis, characterized by iron accumulation, lipid peroxidation, and suppression of the GPX4/xCT system. Notably, CXCL10 expression mirrored the trajectory of ferroptosis. Interventional studies established CXCL10 as an upstream initiator, rather than a consequence, of the ferroptotic process. Mechanistically, we demonstrated that CXCL10 activates STAT3 through the CXCR3 receptor; activated STAT3 then acts as a transcriptional repressor to downregulate the cystine transporter xCT, thereby triggering ferroptosis. This molecular cascade resulted in a significant loss of spinal GABAergic neurons, which could be partially reversed by CXCL10 inhibition. Collectively, our findings uncover a novel mechanism of NP maintenance, wherein the CXCL10/CXCR3/STAT3 axis disrupts the spinal excitation-inhibition balance by promoting ferroptosis-mediated loss of inhibitory neurons. These results offer a fresh perspective on NP pathology and identify this signaling axis as a promising therapeutic target.