Biochanin A suppresses ferroptosis after traumatic brain injury via the Nrf2/HO-1 signaling pathway

Abstract Traumatic brain injury can induce ferroptosis, which plays an important role in TBI progression. Therapies targeting ferroptosis are beneficial for TBI recovery. Biochanin A can be isolated from Huangqi, which has been shown to exert anti-inflammatory and antioxidant effects. Nevertheless, the underlying mechanism of BCA on secondary injury after TBI remain unclear. This study aimed to investigate the mechanism by which BCA regulates ferroptosis after TBI. The mouse TBI model and HT-22 cells were utilized to study the protective effect of BCA on the injury induced by ferroptosis after TBI. Through in vivo experiments, a mouse TBI model was established to determine that BCA could reduce post-TBI injury and exert neuroprotective effects as determined by the Modified Neurological Severity scale, brain water content, Nissl staining, hematoxylin-eosin staining, TUNEL staining. BCA was proven to be capable of inhibiting the changes in post-TBI ferroptosis-related proteins, activating the Nrf2/HO-1 signaling pathway, and reducing oxidative stress, as confirmed by Western blotting. In vitro, erastin-induced ferroptosis in HT-22 cells was attenuated by BCA, as shown increased cell viability, reduced reactive oxygen species and and lipid peroxidation, and restored antioxidant levels. BCA suppressed protein levels of multiple ferroptosis-associated markers in this cell model. In conclusion, BCA had a neuroprotective effect after TBI by inhibiting ferroptosis via activating the Nrf2/HO-1 pathway. These findings may provide potential therapeutic strategies for TBI.