The mechanism of hypoxia-inducible factor-1α enhancing the transcriptional activity of transferrin ferroportin 1 and regulating the Nrf2/HO-1 pathway in ferroptosis after cerebral ischemic injury

• Published in: Neuroscience 2024-11, Vol.559, p.26-38
• Main Authors: Yao, Haiqian, Tian, Jianan, Cheng, Shi, Dou, Haitong, Zhu, Yulan
• Format: Article
• Language: English
• Subjects: Cerebral ischemic injury; Ferroportin 1; Hypoxia-inducible factor-1α; Neurons; Nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway; Oxygen-glucose deprivation
• ISSN: 0306-4522; 1873-7544; 1873-7544
• DOI: 10.1016/j.neuroscience.2024.08.025

[Display omitted] •HIF-1α eases OGD/R −induced ferroptosis.•HIF-1α enhances the transcriptional activity of transferrin FPN1.•FPN1 knockdown annuls HIF-1α-induced alleviation on OGD/R-induced ferroptosis.•HIF-1α boosts FPN1 to activate Nrf2/HO-1 and ease OGD/R-induced ferroptosis.•HIF-1α boosts FPN1 to activate Nrf2/HO-1 and ease cerebral I/R injury in rats. Cerebral ischemic/reperfusion (I/R) injury has high disability and morbidity. Hypoxia-inducible factor-1α (HIF-1α) may enhance the transcriptional activity of transferrin ferroportin 1 (FPN1) in regulating ferroptosis after cerebral ischemia injury (CII). In this study, cerebral I/R injury rat models were established and treated with pcDNA3.1-HIF-1α, pcDNA3.1-NC lentiviral plasmid, or ML385 (a specific Nrf2 inhibitor). Additionally, oxygen-glucose deprivation/reoxygenation (OGD/R) exposed PC12 cells were used as an in vitro model of cerebral ischemia and treated with pcDNA3.1-HIF-1α, si-FPN1, or ML385. The results elicited that cerebral I/R injury rats exhibited increased Longa scores, TUNEL and NeuN co-positive cells, Fe2+ concentration, ROS and HIF-1α levels, and MDA content, while reduced cell density and number, GSH content, and GPX4 protein level. Morphologically abnormal and disordered hippocampal neurons were also observed in CII rats. HIF-1α inhibited brain neuron ferroptosis and ameliorated I/R injury. HIF-1α alleviated OGD-induced PC12 cell ferroptosis. OGD/R decreased FPN1 protein level in PC12 cells, and HIF-1α enhanced FPN1 transcriptional activity. FPN1 knockdown reversed HIF-1α-mediated alleviation of OGD/R-induced ferroptosis. HIF-1α activated the Nrf2/HO-1 pathway by enhancing FPN1 expression and alleviating OGD/R-induced ferroptosis. Conjointly, HIF-1α enhanced the transcriptional activity of FPN1, activated the Nrf2/HO-1 pathway, and inhibited ferroptosis of brain neurons, thereby improving I/R injury in CII rats.