SAE is a widespread brain dysfunction without a clear central nervous system (CNS) infection and the primary symptom is a disturbance of awareness level [1], [2]. In general, the possible mechanisms of SAE include neuroinflammation, abnormal blood–brain barrier (BBB) permeability and oxidative stress [3]. These mechanisms have an impact on normal vascular circulation, neuron transmission and brains normal signaling pathways. Despite significant research into the molecular mechanism and therapy of SAE, it is still a problem worthy of clinical investigation.

Ferroptosis is a relatively novel type of programmed cell death, and iron accumulation and lipid peroxidation are typically present during the process of cell death [4]. According to recent investigations, ferroptosis is implicated in the pathophysiological process of many disorders, including liver cancer [5], renal failure [6], cardiomyopathy [7], and neurodegenerative disease [8], [9], [10]. However, the significance of ferroptosis in the pathogenesis of SAE remains unknown.

In fact, ferroptosis is a crucial pathologic cell death in cerebral hemorrhage, stroke, and other acute brain injuries [11]. A number of studies have found a connection between ferroptosis and sepsis. Li et al. reported that ferritinophagy-mediated ferroptosis contributes to sepsis-induced cardiac injury [12]. According to Wei et al., ALOX12 mediated-ferroptosis and mitochondrial function are implicated in LPS-treated hepatocytes and CLP-induced septic mice [13]. In addition, Li et al. also revealed that Hydrogen sulfide attenuated ferroptosis in sepsis-induced acute lung injury [14]. These data showed that ferroptosis inhibition may be a novel pathophysiological mechanism of sepsis. Although there are some reports about the involvement of ferroptosis in sepsis-associated organs injury, it is unknown if ferroptosis plays a role in the pathogenesis of sepsis-associated fencephalopathy. The aim of this study is to confirm the role of ferroptosis in the pathogenesis of SAE and demonstrate that suppressing ferroptosis protects against SAE by reducing cognitive impairment, blood–brain barrier disruption, and neurological abnormalities.