Ferulic acid activates Nrf2/HO-1 signaling axis to ameliorate neuronal Golgi stress by SKP2

Traumatic brain injury (TBI) ranks among the top contributors to neurological impairments worldwide, with Golgi stress implicated in neuronal injury. This study investigated the neuroprotective effects of ferulic acid (FA) in TBI by regulating Golgi stress. HT-22 and NSC34 cells were exposed to H 2 O 2 to induce a neuronal injury model. Protein expression were evaluated via Western blot and immunofluorescence. Cell viability and apoptosis were quantified using CCK-8 assay and TUNEL staining, respectively. The interactions between Src, SKP2, and Nrf2 were detected by Co-IP assay. FA treatment reduced LDH release, as well as repressed Golgi stress and apoptosis by H 2 O 2 -induced in HT-22 and NSC34 cells. Mechanistically, FA inhibited Src-mediated phosphorylation of SKP2 at Y131, preventing SKP2-mediated Nrf2 ubiquitination and degradation. Moreover, FA activated the antioxidative Nrf2/HO-1 pathway, alleviating H 2 O 2 -induced Golgi stress and neuronal injury. FA reduced neuronal Golgi stress in H 2 O 2 -treated neuronal cells by restoring the Nrf2/HO-1 signaling through inhibiting Src-mediated SKP2 phosphorylation. These findings indicate that FA is a potential neuroprotective agent.