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. Following spinal cord injury (SCI), secondary damage is driven by a vicious cycle of ferroptosis and neuroinflammation. This positive feedback loop—where iron-dependent lipid peroxidation releases DAMPs to fuel microglial activation, and inflammatory cytokines exacerbate oxidative cell death—propels irreversible neurological deficits. Tetramethylpyrazine (TMP), a bioactive alkaloid from Ligusticum chuanxiong, disrupts this pathological crosstalk by functioning as a spatiotemporal “pathway crosstalk” modulator. TMP exerts bidirectional control over two opposing signaling axes: Nrf2/ARE Activation (Acute Phase, 0–24 h): TMP facilitates Keap1 modification and ROS scavenging, stabilizing Nrf2 and driving the expression of antioxidant and anti-ferroptotic genes (xCT, GPX4, HO-1, FTH1). This suppresses early lipid peroxidation and iron overload, preserving vulnerable neurons and oligodendrocytes. JNK/AP-1 Inhibition (Subacute-to-Chronic Phase, 24 h–14 d): By blocking ASK1 activation and downstream JNK phosphorylation, TMP reduces AP-1-driven transcription of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and pro-apoptotic factors (Bax). This curbs M1 microglial polarization, attenuates glial scar formation, and resolves neuroinflammation. Through this time-sequential dual regulation—early inhibition of ferroptosis followed by sustained anti-inflammation—TMP transforms the injury microenvironment from a cytotoxic to a pro-regenerative niche. This enables axonal sparing, remyelination, and eventual motor recovery, embodying a therapeutic paradigm shift from antioxidant damage control toward active regenerative repair. Key takeaway for the graphical figure: A central timeline figure showing the reciprocal ferroptosis-inflammation loop being interrupted by TMP, with Nrf2 and JNK as two balanced scales—TMP tilting the balance toward neuroprotection and functional recovery.