SAE is a diffuse brain dysfunction characterized by a progressively developing state of sepsis (Spapen et al., 2010). The incidence and mortality rates of SAE exhibit a correlated association with the occurrence of sepsis, constituting an essential nexus within the purview of this neurobiological investigation (Ho et al., 2016). Despite the growing evidence of research dedicated to SAE, the precise mechanisms underlying the onset and progression remain elusive (D'Avila et al., 2013). Furthermore, its treatment is primarily palliative, lacking effective preventative or therapeutic measures. Abnormal cognitive decline of SAE occurs in the hippocampus which is responsible for memory and emotional control (Xu et al., 2022). A significant positive correlation between spatial memory acquisition and extent of complexity of CA1in the hippocampus was found (Çetereisi et al., 2019). Inflammation has been widely recognized as a key player in the development cognitive impairments associated with SAE (Haileselassie et al., 2020). Hence, an exploration of the pathogenesis of SAE-associated cognitive decline will provide novel strategies for its treatment.

The hyperactivation of pro-inflammatory cytokines, culminating in the accumulation of unfolded or misfolded proteins within the endoplasmic reticulum. This mechanistic cascade assumes significance in the investigated pathophysiological milieu, underlining a pivotal aspect of our neurobiological inquiry (Labrie et al., 2022), prolonged stress can lead to severe cellular damage and even apoptosis (Chen et al., 2017; So et al., 2012). Additionally, ERS can activate inflammatory signals in damaged cells, thereby enhancing the inflammatory response. This creates a positive feedback loop between ERS and neuroinflammation, leading to secondary damage (Oslowski et al., 2012). The endoplasmic reticulum instigates three signaling pathways, orchestrated by resident protein folding sensors, namely inositol-requiring enzyme 1 alpha (IRE1α), PKR-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Among these pathways, IRE1α abbreviated as IRE1, functions as a serine/threonine kinase and endoribonuclease. It represents the most evolutionarily conserved branch of the unfolded protein response (UPR) signaling, governing cellular fate under ERS conditions (Lhomond et al., 2022), IRE1α undergoes autophosphorylation in response to ERS, activating its ribonuclease activity and allowing it to splice X-box binding protein 1 (XBP1) to generate spliced XBP1 (XBP1s). Meanwhile, the excessive activation of ERS leads to calcium release and oxidative stress, thereby initiating downstream cascades that result in inflammation (Maly and Papa, 2014). Current research has already indicated that IRE1α signaling can be employed for the treatment of various diseases, such as diabetes (Ozcan et al., 2004), myocardial infarction (Bi et al., 2018), and neurodegenerative diseases (Dunys et al., 2014). However, its involvement in the pathogenesis of SAE remains unclear. Recent study have shown that IRE1α interacts with MAM to regulate calcium transfer from the endoplasmic reticulum to mitochondria (Son et al., 2014). Mitochondria-associated membranes (MAM) disorders have received a great deal of attention in the pathogenesis and pathology of encephalopathies, and changes in the behavior of MAM may be related to various dysfunctions in the brain, such as mitochondrial damage, ERS, and calcium metabolism (Jiang et al., 2023).

4-Phenylbutyrate (4-PBA) is a bioaromatic fatty acid that is prescribed for the treatment of patients with urea cycle disorders based on its ability to act as an ammonia scavenger (Brusilow and Maestri, 1996). Additionally, 4-PBA exerts antitumor effects via acting as a histone deacetylase inhibitor and regulating gene transcription (Lopez et al., 2007). In recent years, 4-PBA has been found to have anti-ERS properties (Koyama et al., 2014). However, this mechanism is not fully understood. Some studies have reported that it is related to anti-oxidative stress (Zeng et al., 2014). Moreover, analysis of 4-PBA treated BV2 cells and animals in SAE revealed IRE1α-XBP1 axis activation. Based on these results, multiple approaches were used to explore the effects of inhibition of the IRE1α-XBP1 axis in SAE on cell viability and mitochondrial function and to estimate the underlying mechanisms. Therefore, we hypothesize that 4-PBA, an ERS inhibitor, may protect vital organ functions and be beneficial for alleviating the treatment of SAE. The mechanism may be associated with the inhibition of ERS-mediated inflammatory responses, oxidative stress, and intracellular calcium influx.