Sepsis, a life-threatening syndrome triggered by infections, leads to profound physiological, pathophysiological, and biochemical disturbances. Sepsis claims approximately 5.3 million lives annually, making it a major global public health crisis (Rudd et al., 2020; Singer et al., 2016). Among its many complications, sepsis-associated encephalopathy (SAE) stands out as a particularly severe neurological manifestation, marked by widespread cerebral dysfunction. SAE significantly contributes to increased mortality and persistent cognitive deficits in survivors (Iwashyna et al., 2010). Despite its clinical impact, effective treatments remain elusive, with no targeted therapeutic options currently available (Iwashyna et al., 2010; Sonneville et al., 2023).

The pathophysiology of SAE is complex and multifactorial. One of the key contributors to cognitive decline in SAE is the disruption of the BBB (Ren et al., 2020). The BBB, composed of brain endothelial cells (bECs), pericytes, astrocytes, and the basement membrane, acts as a crucial gatekeeper, regulating the passage of substances and the infiltration of inflammatory mediators into the central nervous system (Hill et al., 2025; Yoon et al., 2025). While much of the research has focused on immune cell-mediated inflammation (Jing et al., 2022, 2025), recent studies suggest that pyroptosis of bECs may play a critical role in BBB breakdown. Classical pyroptosis relies on the activation of caspase-1 by inflammasomes (such as NLRP3), which leads to the maturation and release of interleukin-1β (IL-1β) and interleukin-18 (IL-18), as well as the cleavage of gasdermin D (GSDMD) (Ding et al., 2022; Yoon et al., 2025). In contrast, non-canonical pyroptosis is directly triggered by intracellular lipopolysaccharide (LPS), which activates caspase-11. Subsequently, caspase-11 cleaves gasdermin D (GSDMD) to form membrane pores. Upon LPS stimulation (Shi et al., 2014), LPS induces caspase-11/GSDMD-dependent non-canonical pyroptosis in bECs. This process leads to the disruption of tight junction proteins, the detachment of endothelial cells from the basement membrane, and the destruction of the BBB ultrastructure. As a result, a route is established for peripheral inflammatory factors to infiltrate the central nervous system, exacerbating neuroinflammation and cognitive impairment (Wei et al., 2024). This discovery indicates that pyroptosis of non-immune cells, particularly non-canonical pyroptosis of bECs, might be an underestimated yet critical factor in the pathogenesis of SAE. Consequently, inhibiting the non-canonical pyroptosis pathway to safeguard bEC function offers a novel potential intervention strategy for the prevention and treatment of SAE.

Rosmarinic acid (RA), the principal polyphenol in diverse medicinal plants, exhibits activities including anti-inflammation and anti-oxidation, and demonstrates protective effects against various nervous system disorders (Noor et al., 2022). Multiple studies have indicated that RA can suppress the NLRP3-Caspase-1-GSDMD pathway and the release of IL-1β/IL-18, thereby presenting anti-pyroptosis properties (Akhter et al., 2022; Feng et al., 2025). Simultaneously, there is evidence supporting the role of RA in safeguarding endothelial function and the BBB(Cui et al., 2018) (Zhou et al., 2017). Herein, we hypothesize that RA might possess potential protective effects in SAE-related cognitive impairment. This investigation aims to validate the therapeutic efficacy and underlying mechanism of RA on SAE-induced cognitive dysfunction in animal models. Thus, in the present research, we aimed to determine whether RA can mitigate SAE-related cognitive impairment, and to examine whether its potential therapeutic effects may be associated with modulating neuroinflammation and preserving BBB integrity. We evaluated microglial inflammatory responses in the hippocampus and the involvement of the caspase-11/GSDMD pathway in bECs using an LPS-induced model of SAE. This study assesses the efficacy of RA using an animal model and delves into its molecular mechanism, thereby providing a foundation for the future treatment of inhibiting non-immune cell.