<p>Following peripheral nerve injury (PNI), the ferroptosis-inflammation axis restricts the neural repair process. As a critical neuroregenerative factor, the mechanism by which CXCL12 promotes nerve repair by regulating the ferroptosis-inflammation axis remains unclear. This study systematically investigated the mechanism of CXCL12 using a combination of clinical samples, as well as cellular and animal experimental models. Clinical data showed that CXCL12 levels in the serum of PNI patients were significantly elevated at 72 hours post-surgery, suggesting its potential involvement in the early regulatory process following nerve injury. In an LPS-induced Schwann cell (SC) injury model, CXCL12 effectively inhibited the occurrence of ferroptosis by activating the ERK/Nrf2 signaling pathway, which led to reduced cellular Fe²⁺ accumulation, downregulation of ACSL4, and upregulation of GPX4 and FSP1 expression. Further investigation revealed that the alleviation of cellular ferroptosis was accompanied by a decrease in NF-κB pathway activity, characterized by reduced levels of p-NF-κB and p-IκBα, as well as decreased secretion of TNF-α and IL-1β, indicating that CXCL12 possesses anti-inflammatory effects. Rescue experiments demonstrated that the ERK inhibitor U0126 partially reversed the anti-ferroptotic effect of CXCL12. Iron overload experiments (FAC) weakened the anti-inflammatory effect of CXCL12, whereas Ferrostatin-1 mimicked its anti-inflammatory action, suggesting that ferroptosis plays a pivotal role in the anti-inflammatory effects of CXCL12. Additionally, overexpression of NF-κB also diminished the anti-inflammatory efficacy of CXCL12. Animal experiments further confirmed that CXCL12 improved the mitochondrial structure of nerve tissues following PNI, reduced the accumulation of Fe²⁺ and lipid peroxidation, and promoted axonal and myelin regeneration. In conclusion, CXCL12 inhibits SC ferroptosis and reduces intracellular Fe²⁺ accumulation via the ERK/Nrf2 pathway, thereby attenuating the NF-κB-mediated inflammatory response and promoting nerve repair after PNI.</p>