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

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.

This study was supported by National Science Basic Research Program of Shaanxi (Grant No. 2023-JC-QN-0958), Basic Research program of Xi’an Municipal Health Commission (Grant No. 2024qn21), and the Foundation of Xi’an International Medical Center Hospital (Grant Nos. 2021QN013 and 2021QN026). Yuehuan Hu and Mingxia Zhang These authors contributed to the work equally and should be regarded as co-first authors. Clinical Experimental Center, Xi’an Engineering Technology Research Center for Cardiovascular Active Peptides, Northwest University Affiliated Xi’an International Medical Center Hospital, Xi’an, Shaanxi, China Yuehuan Hu, Mingxia Zhang, Hui Zhao, Yao Ruan & Tian Liu Pathology Department, Northwest University Affiliated Xi’an Chest Hospital, Xi’an, Shaanxi, China The authors declare no competing interests.

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