Reduced Arpc1b expression in astrocytes is associated with cytoskeletal remodeling, ALDOA redistribution, glycolysis, and neuroinflammation in a mouse model of bone cancer pain.

BACKGROUND: Bone cancer pain (BCP) frequently develops following cancerous lesions in the bone, severely affecting patients' daily activities and long-term quality of life. However, effective therapeutic options remain limited. Therefore, it is essential to explore its underlying mechanisms to identify new therapeutic targets. METHODS: A mouse model of BCP was established to investigate pain development using the von Frey test. Immunofluorescence staining and Western blotting were performed to detect neuroinflammation and astrocyte activation. Transcriptome sequencing and targeted metabolomics were conducted to identify significantly altered genes and pathways in BCP mice, and the results were validated by Western blotting, enzyme-linked immunosorbent assay, and immunofluorescence staining. Small interfering RNA was used to examine the relationship between Arpc1b and ALDOA using the aforementioned methods. RESULTS: Neuroinflammation in the spinal cord of BCP mice was accompanied by activation of C3-positive reactive astrocytes. Sequencing analysis revealed that Arpc1b and glycolysis were associated with C3-positive astrocyte activation. Further experiments demonstrated that BCP-induced neuroinflammation downregulated Arpc1b and increased the expression of glycolytic enzymes in spinal cord astrocytes. Additionally, increased soluble ALDOA appeared to contribute to BCP-induced glycolysis in astrocytes, while Arpc1b-mediated cytoskeletal remodeling increased free ALDOA levels. CONCLUSIONS: The significant reduction of Arpc1b in C3-positive astrocytes within the spinal cord of BCP mice mediates cytoskeletal remodeling, causing dissociation of ALDOA from F-actin. This process promotes excessive glycolysis in astrocytes and persistent neuroinflammation, which may underlie BCP.