Tetramethylpyrazine modulates the Nrf2/JNK axis to intervene in ferroptosis and neuroinflammation after spinal cord injury: an integrated perspective from antioxidant to regenerative therapy.

The interplay between ferroptosis and neuroinflammation during secondary injury after spinal cord injury (SCI) critically drives permanent neurological dysfunction. Targeting both processes simultaneously is a promising therapeutic strategy. Tetramethylpyrazine (TMP), the main active component of Ligusticum chuanxiong, exhibits multi-target neuroprotective properties. This review systematically summarizes TMP's role in inhibiting ferroptosis and neuroinflammation after SCI by modulating the Nrf2/JNK signaling axis. We first outline TMP's chemical structure, bioavailability, and protective effects in SCI models. Next, we elucidate the Nrf2/ARE pathway as a hub for anti-ferroptosis defense and the JNK/AP-1 pathway as a driver of inflammation and apoptosis. We then explore crosstalk between these pathways via ROS, Trx-1, and p62. Existing evidence positions TMP as a "pathway crosstalk" modulator that activates Nrf2 and inhibits JNK through multiple mechanisms, including Keap1/ASK1 modification, ROS scavenging, and adaptor protein regulation. From a spatiotemporal perspective, we analyze the phased evolution of ferroptosis and inflammation, proposing TMP's time-sequential dual regulation: early-phase anti-ferroptosis and late-phase anti-inflammation. Finally, we identify current research limitations in mechanistic depth, pathway crosstalk evidence, and translational studies, and offer future directions. This review provides an integrated viewpoint for TMP in SCI treatment, a paradigm for understanding multi-target natural products, and a theoretical foundation for shifting from antioxidant to pro-regenerative strategies.