CD74 Affects Ferroptosis in Traumatic Brain Injury by Modulating the Nrf2/HO-1 Signaling Pathway.
Sun GuangWei, Li Jie, Wang Meng, Lu Kun, Liu DanDan, Hu ChangLong, Qiu Tao
Abstract
OBJECTIVE: This study aimed to explore whether CD74 participates in regulating ferroptosis and to clarify the related mechanisms in traumatic brain injury (TBI). METHODS: A TBI rat model was generated using controlled cortical impact. The ferroptosis inducer RSL-3, the inhibitor Liproxstatin-1 (Lip-1), and lentiviral vectors targeting CD74 or Nrf2 were injected into the lateral ventricle. Knockdown efficiency of the lentiviral vectors was verified by RT-qPCR. Motor performance was evaluated using the foot fault test, neurobehavioral function via mNSS scoring, brain water content using the wet-dry method, iron deposition in cortical tissues by Perls' Blue staining, Fe2+ levels with an iron assay kit, degenerating neurons by Fluoro-Jade C staining, and Nrf2/HO-1 pathway protein expression via Western blot. RESULTS: TBI rats displayed increased foot faults, elevated mNSS scores, increased brain water content, higher Fe2+ levels, more iron-positive cells, and greater numbers of degenerating neurons in the cerebral cortex. Lip-1 or CD74 downregulation alleviated TBI-related changes, whereas RSL-3 or CD74 upregulation worsened them. Downregulating CD74 enhanced Nrf2/HO-1 pathway activity, and Nrf2 knockdown counteracted the benefits of CD74 downregulation. CONCLUSION: Reducing CD74 expression ameliorates ferroptosis in TBI by activating the Nrf2/HO-1 signaling axis.
Key Findings
- CD74 modulates ferroptosis in traumatic brain injury (TBI) by affecting the Nrf2/HO-1 signaling pathway.
- Downregulation of CD74 alleviates TBI-induced motor and neurobehavioral deficits, brain edema, iron accumulation, and neuronal degeneration.
- Activation of the Nrf2/HO-1 pathway mediates the protective effects of CD74 downregulation, while Nrf2 knockdown reverses these benefits.
Clinical Significance
Targeting CD74 to activate the Nrf2/HO-1 pathway may offer a therapeutic strategy to reduce ferroptosis and improve outcomes in patients with traumatic brain injury.
Citation
Sun GuangWei, Li Jie, Wang Menget al.. CD74 Affects Ferroptosis in Traumatic Brain Injury by Modulating the Nrf2/HO-1 Signaling Pathway. The journal of gene medicine. 2026-May.