A novel TCF12-MAVS signaling axis in astrocytes promotes vincristine-induced neuropathic pain in male mice

Brain Behav Immun. 2026 May 20:106829. doi: 10.1016/j.bbi.2026.106829. Online ahead of print.

ABSTRACT

Chemotherapy-induced neuropathic pain (CINP) can be triggered by microtubule-targeting agents, including plant-derived vinca alkaloids such as vincristine (VCR). In a male mouse model of VCR-induced neuropathic pain (VINP), mitochondrial antiviral signaling protein (MAVS) expression was upregulated in the spinal cord. Suppression of MAVS significantly increased the pain threshold, alleviated persistent vincristine-induced hyperalgesia, and ameliorated mitochondrial damage in the spinal cord. Through bioinformatic analysis, transcription factor 12 (TCF12) was identified as a transcription factor with high binding potential to the MAVS gene promoter. Dual-luciferase reporter and electrophoretic mobility shift assays (EMSA) confirmed that TCF12 binds to the MAVS promoter region and promotes its transcriptional activation. Furthermore, immunofluorescence double staining demonstrated TCF12 localization in spinal astrocytes of VCR-treated male mice. Knockdown of TCF12 via siRNA attenuated chemotherapy-induced mechanical allodynia and thermal hyperalgesia, and reduced MAVS expression. Notably, in VCR-treated primary astrocytes, GFAP fluorescence intensity was increased and showed enhanced co-localization with TCF12. Silencing either TCF12 or MAVS elevated the mitochondrial membrane potential in primary mouse astrocytes and reduced the levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and CXCL1. In summary, our study reveals that the TCF12-MAVS signaling axis plays a critical role in the development of VINP. Inhibition of this pathway alleviates neuropathic pain and mitochondrial injury caused by chemotherapeutic agents, providing new potential targets and molecular insights for the prevention and treatment of VINP.

PMID:42167547 | DOI:10.1016/j.bbi.2026.106829