Herbacetin alleviates ferroptosis via Hif-1α/SLC7A11/GPX4 axis in traumatic brain injury.

An increasing body of evidence indicates that ferroptosis, characterized by lipid peroxidation (LPO), plays a significant role in the neurophysiological and pathological changes following traumatic brain injury (TBI). Herbacetin (HBT), primarily derived from Sedum plants, is hypothesized to possess strong antioxidant activity due to the presence of five phenolic hydroxyl groups in its structure, which may allow it to counteract ferroptosis after TBI, thereby offering a potential therapeutic approach for TBI treatment. In our study, we employed an erastin and RSL3-induced ferroptosis model using HT22 and PC12 cells. Our findings demonstrated that HBT significantly mitigates erastin-induced cell death by reducing reactive oxygen species (ROS) levels, LPO, and Fe2+ accumulation. Moreover, HBT protected against changes in mitochondrial membrane potential and mitochondrial superoxide levels induced by erastin and RSL3. We further confirmed HBT's ability to inhibit ferroptosis in the TBI mouse model. HBT reduced the levels of LPO and iron deposition in the tissue surrounding the injury site after TBI, protected neurons, and decreased microglial activation. Mechanistically, we showed that HBT upregulates hypoxia inducible factor-1α (Hif-1α) expression in both ferroptosis cells and the TBI animal model, which in turn leads to the upregulation of recombinant solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), thereby reducing ferroptosis. RNA-seq analysis and Hif-1α knockdown experiments in HT22 cells supported this conclusion. In conclusion, our findings provide a potential therapeutic basis for the clinical use of HBT in preventing neuronal ferroptosis following TBI.