CXCL12 Promotes Peripheral Nerve Injury Repair by Inhibiting the Ferroptosis‒Inflammation Axis via the ERK/Nrf2 Pathway

Peripheral nerve injury (PNI) is often limited by the activation of the ferroptosis‒inflammation axis. Although CXCL12 is a crucial neuroregenerative factor, the precise mechanism by which it promotes nerve repair through regulating this axis remains unclear. This study systematically investigated the role and underlying mechanism of CXCL12 via clinical samples, cell models, and animal experiments. Clinical data revealed a significant increase in serum CXCL12 levels in PNI patients, suggesting its potential involvement in nerve injury regulation. In an LPS-induced Schwann cell (SC) injury model, CXCL12 attenuated ferroptosis and oxidative damage by activating the ERK/Nrf2 signaling pathway to upregulate GPX4 and FSP1 while suppressing ACSL4 expression. Concurrently, CXCL12 inhibited the activation of the NF-κB signaling pathway, thereby reducing the secretion of TNF-α and IL-1β and alleviating the inflammatory response. The antiferroptotic effect of CXCL12 was reversed by the ERK inhibitor U0126. Furthermore, ferrous ammonium citrate (FAC)-induced iron overload experiments confirmed that ferroptosis is a critical mechanism bridging CXCL12 regulation of inflammation and that NF-κB overexpression weakens its anti-inflammatory effects. In animal experiments further demonstrated that CXCL12 improved the mitochondrial structure, reduced the accumulation of Fe2+ and lipid peroxidation in injured nerve tissue, and promoted axon and myelin regeneration after PNI. Overall, CXCL12 promotes PNI repair by activating the ERK/Nrf2 pathway to inhibit SC ferroptosis, which subsequently downregulates the NF-κB-mediated inflammatory response. This study is the first to elucidate the bridging role of ferroptosis in CXCL12-mediated inflammation regulation, suggesting a new theoretical basis for targeting CXCL12 as a potential therapeutic strategy for PNI.