CD74 Affects Ferroptosis in Traumatic Brain Injury by Modulating the Nrf2/HO-1 Signaling Pathway

This study aimed to explore whether CD74 participates in regulating ferroptosis and to clarify the related mechanisms in traumatic brain injury (TBI).

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.

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.

Reducing CD74 expression ameliorates ferroptosis in TBI by activating the Nrf2/HO-1 signaling axis.