Neuroreport. 2026 Mar 18;37(5):167-180. doi: 10.1097/WNR.0000000000002250. Epub 2026 Feb 17.
ABSTRACT
BACKGROUND: Ferroptosis is emerging as a crucial type of cellular demise involved in intracerebral hemorrhage (ICH). Cysteine desulfurase (NFS1) is a key gene involved in the regulation of ferroptosis; however, its role in modulating neuronal ferroptosis in ICH remains unclear. This work aimed to explore whether NFS1 influences neuronal ferroptosis in ICH and to explore the underlying molecular mechanisms.
METHODS: We established an ICH animal model using collagenase injection and a cellular model by treating neurons with hemin. Neurons with NFS1 overexpression or knockdown were generated using adenoviral vectors. Ferroptosis was evaluated by measuring typical indicators such as lipid peroxidation and ferrous iron levels. In-vivo NFS1 overexpression was achieved via adeno-associated virus constructs. Neurobehavioral function was assessed using Rotarod, Cylinder, and Corner tests.
RESULTS: A marked decrease in NFS1 levels was revealed in both animal and cellular models. Overexpression of NFS1 inhibited hemin-induced neuronal damage and ferroptosis. The exacerbating impact of NFS1 silencing on hemin-induced neuronal damage could be reversed by inhibiting ferroptosis. NFS1 overexpression suppressed hemin-induced neuronal ferroptosis by inhibiting the iron-responsive element-binding protein 2-mediated iron-starvation response. Blocking the iron-starvation response reversed the promoting effect of NFS1 silencing on neuronal ferroptosis. In the animal model, NFS1 overexpression significantly reduced hemorrhage volume and improved neurobehavioral function, accompanied by lower levels of iron-starvation response and ferroptosis.
CONCLUSION: NFS1 may alleviate ICH damage by suppressing neuronal ferroptotic death via the downregulation of the iron-starvation response, suggesting a prospective therapeutic target for the treatment of this disorder.
PMID:41870900 | DOI:10.1097/WNR.0000000000002250