Deferoxamine attenuates bone cancer pain via modulation of the RIG-I/CCL5 signaling pathway in rats.

Bone cancer pain (BCP) severely compromises the quality of life, and its molecular mechanisms are not fully understood. Increasing evidence implicates spinal iron overload in pain-related neuroinflammation, with the chemokine CCL5 acting as a critical mediator. Given that retinoic acid-inducible gene I (RIG-I) regulates CCL5 expression in pathological conditions, we hypothesized that a spinal Fe2+/RIG-I/CCL5 signaling axis contributes to BCP. Using rat spinal cord neurons in vitro, we found that erastin increased levels of Fe2+, RIG-I, and CCL5, effects that were reversed by the iron chelator deferoxamine. RIG-I knockdown reduced CCL5 expression but did not affect Fe2+ accumulation. In a rat model of BCP, spinal iron accumulation was associated with the development of mechanical allodynia and the upregulation of RIG-I and CCL5; immunofluorescence further revealed that RIG-I was predominantly expressed in spinal neurons. Intrathecal administration of deferoxamine or RIG-I siRNA attenuated pain behaviors and downregulated the expression of both RIG-I and CCL5. These findings demonstrate the spinal Fe2+/RIG-I/CCL5 pathway as a critical promoter of BCP and highlight the potential therapeutic strategies targeting iron chelation or RIG-I signaling.