Authors :
Presenting Author: Tengyue Zhang, PhD – Guangzhou National Lab
Ruili Niu, PhD – Guangzhou National Lab
Yue Gui, MSN – Guangzhou National Lab
Huifeng Li, PhD – Guangzhou National Lab
Guoyun Feng, PhD – Guangzhou National Lab
Yue Xing, BS – Guangzhou
Rationale:
This study aims to elucidate the role of heme oxygenase-1 (HO-1)–mediated ferroptosis in epileptogenesis, and to uncover cell type– and stage–specific mechanisms linking iron dysregulation to seizure development.
Methods:
A cobalt-induced neocortical epilepsy rat model was established. mRNA-seq and single-nucleus RNA sequencing (snRNA-seq) were conducted at 3, 9, and 15 days post-surgery to characterize the spatiotemporal expression of Hmox1 across glial cell populations. HO-1 protein expression, Fe²⁺ deposition, and lipid peroxidation (4-HNE) were assessed using immunohistochemistry and biochemical assays. The therapeutic impact of HO-1 inhibition was evaluated via intracerebral osmotic pump infusion.
Results:
Hmox1 was transiently expressed in both astrocytes and microglia during early epileptogenesis (day 3), but expression became predominantly microglial during the chronic phase (days 9 and 15). Persistent HO-1 upregulation in microglia was associated with pathological iron accumulation, elevated 4-HNE levels, and downregulation of neuronal glutamate transporters. HO-1 inhibition attenuated Fe²⁺ overload and significantly reduced seizure burden.
Conclusions:
These findings identify microglial HO-1–driven ferroptosis as a time-dependent pathogenic mechanism in epileptogenesis. Temporal targeting of glial HO-1 offers a promising strategy to interrupt the iron–ferroptosis–seizure cascade and preserve neuronal homeostasis.
Funding:
This work was funded by the National Natural Science Foundation of China (XFY 82271492，81971202, 81671367, and 81790653), Major Project of Guangzhou National Laboratory (GZNL2024A02001.