Subarachnoid hemorrhage (SAH) is a potentially life-threatening neurosurgical emergency accounting for approximately 5 % of all types of strokes [1]. Although SAH is less common than ischemic stroke and intracerebral hemorrhage, it results in a similar social burden due to the younger average age of patients with SAH [2]. The mobility and mortality rates of SAH remain high despite the development of modern medical technology and treatment in recent decades [3]. Almost one-third of patients with SAH die and one-third of the survivors are disabled as a result. Moreover, many randomized clinical trials have failed to improve the prognosis of patients, making it urgent to establish the pathophysiological process that occurs after SAH [4]. It is well-known that blood is injected into the subarachnoid space through the ruptured intracranial aneurysms after SAH, which is responsible for all pathological events, including increased intracranial pressure, cerebral vasospasm, cerebrovascular microcirculation dysfunction, and brain injury [1,5,6]. Hence, the damaging effects of blood and its degradation products have gained increasing attention [7].

Iron is the one of the main elements of red blood cells, and represents an essential element for all living organisms due to its significant role in oxygen transport, electron transport, redox reactions, and nucleotide biosynthesis, among others [8]. However, iron is a double-edged sword. Owing to the influx of blood into the subarachnoid space, a massive amount of hemoglobin carrying a large quantity of iron is left within the space [1]. Extracellular hemoglobin itself can induce neurotoxicity, mainly via oxidation and inflammation, and the breakdown products of hemoglobin, such as heme or iron, are also highly neurotoxic [7]. Moreover, after the ictus of SAH, extravascular blood does not stay localized, it can spread via cerebrospinal fluid (CSF) into other central nervous system (CNS) areas, which provides a potential iron reservoir for the brain [1,9,10]. Studies have shown that iron accumulation in the brain is one of the most important pathophysiological changes after SAH and the prognosis of SAH is highly related to the severity of iron accumulation [[11], [12], [13], [14]]. Thus, it is of great significance to clarify the exact mechanism underlying iron overload after SAH.

Ferroportin1 (FPN1) is the only known transmembrane protein responsible for exporting iron [15]. Several studies have discovered that a decreased level of FPN1 in the brain may lead to more severe iron accumulation in many diseases such as Alzheimer's disease, Parkinson's disease, and traumatic brain injury [[16], [17], [18], [19]]. FPN1 can be bound by its ligand hepcidin, resulting in endocytosis and proteolysis [15]. Hepcidin, a 25 amino acid peptide predominantly manufactured by hepatocytes, can also be produced by glia cells in the brain [20]. Some researchers have suggested that the altered level of hepcidin contributes to iron accumulation in different diseases [[21], [22], [23]]. However, how exactly hepcidin and FPN1 influence iron accumulation after SAH has not yet been elucidated.

As the essential effectors of transforming growth factor β (TGFβ) family members, Smad transcription factors have multiple functions in many aspects, including neurogenesis, angiogenesis, cancer development, and tissue fibrosis [[24], [25], [26], [27]]. Studies have shown that phosphorylated-Smad1/5 (p-Smad1/5) and Smad4 likely play a regulatory role in the transcription of hepcidin in hepatocytes [28,29]. However, few studies have investigated the role of Smad transcription factors after SAH, with the exception of their possible contribution to hydrocephalus [30].

In this study, we investigated the exact mechanism of iron accumulation after SAH. We demonstrate that astrocyte-derived hepcidin increased significantly after SAH owing to the nuclear translocation of transcription factors p-Smad1/5 and Smad4, which led to a decreased level of neuronal FPN1, aggravation of iron accumulation, and worse neurological outcome.