Microglial HO-1 aggravates neuronal ferroptosis via regulating iron metabolism and inflammation in the early stage after intracerebral hemorrhage.

Heme oxygenase 1 (HO-1), an enzyme involved in heme catabolism, has been shown upregulated in microglia cells and plays a critical roles in neurological damages after intracerebral hemorrhage (ICH). However, the mechanisms by which HO-1 mediates the neuronal damages are still obscure. Here, our findings demonstrate that HO-1 over-expression exacerbates the pro-inflammatory response of microglia and induces neuronal ferroptosis through promoting intracellular iron deposition in the ICH model both in vitro and in vivo. Furthermore, in the co-cultured ICH model in vitro, we verify that HO-1 over-expression disrupts the balance of iron metabolism in microglia, which increases the iron efflux to the extracellular space and promotes iron ion uptake in neurons, leading to lipid peroxidation injury and further contributing to neuronal ferroptosis. Moreover, the specific ferroptosis inhibitor Ferrostatin-1 (Fer-1) treatment could mitigate the damages in the co-cultured HT22 cells that caused by HO-1 over-expression in microglia, and improve the neurological function in the ICH model in mice. By shedding light on the mechanisms of aggravating neuronal ferroptosis due to HO-1 overexpression in the early stages after ICH, our study provides insights into the potential therapy of targeting HO-1 to treat ICH.