Work

A spinal USP7-Bach1 positive feedback loop drives NOX4-mediated ferroptosis in neuropathic pain

Year: 2026

Type: article

Abstract: Neuropathic pain is a chronic condition caused by somatosensory system lesions, characterized by persistent hypersensitivity and limited therapeutic options. While oxidative stress and ferroptosis contribute to pain progression, the upstream regulators that orchestrate these redox events remain largely undefined. Here, we identify the transcription factor Bach1 as a key regulator of ferroptosis in the spinal cord. Following peripheral nerve injury, Bach1 expression was markedly upregulated in spinal neurons. Bach1 directly bound to the NOX4 promoter and enhanced its transcription, leading to excessive reactive oxygen species (ROS) generation and lipid peroxidation. We further found that the deubiquitinase USP7 interacted with Bach1 and promoted its stability through deubiquitination. In turn, Bach1 transcriptionally upregulated USP7, forming a positive feedback loop that sustained redox dysregulation and pain hypersensitivity. Inhibition of the USP7-Bach1-NOX4 axis attenuated ferroptosis and alleviated neuropathic pain. Together, these findings delineate a USP7-Bach1-NOX4 signaling axis that links post-translational stabilization to transcriptional activation in spinal ferroptosis and identify potential therapeutic targets for neuropathic pain.

Source: Redox Biology

DOI: 10.1016/j.redox.2026.104153