Propofol Attenuates LPS-induced Inflammation by Suppressing the Activation of Histone Lactylation in hCMEC/D3 Cells

Introduction: Neuroinflammation is recognized as one of the pathogenic mechanisms underlying sepsis-associated encephalopathy (SAE). As the most commonly used anesthetic agent in the perioperative period, propofol has been demonstrated to exhibit neuroprotective and anti-inflammatory effects. This study aimed to investigate whether propofol could mitigate lipopolysaccharide (LPS)-mediated neuroinflammation and to explore the potential mechanisms. Methods: hCMEC/D3 cells were treated with propofol, followed by LPS exposure. Western blot, ELISA, and RT-qPCR were used to assess the expression (both protein and mRNA levels) of potential pathway participants. Intracellular Fe2+ levels were determined using an Iron Assay Kit. In addition, an in vitro blood-brain barrier (BBB) model was constructed by co-culturing hCMEC/D3 cells and human astrocytes, and BBB permeability was assessed by measuring trans-endothelial electrical resistance (TEER). Results: LPS (50 μg/mL, 1 h) significantly increased the secretion of TNF-α and IL-1β, induced intracellular Fe2+ accumulation, and upregulated the expression of 4-HNE, H3K18la, pan-Kla, and LDHA, while decreasing the expression of ZO-1, Claudin-5, and Occludin in hCMEC/D3 cells. More importantly, propofol (25 μM, 2 h) alleviated the aforementioned effects of LPS on hCMEC/D3 cells. Furthermore, we observed significant LPS-induced TEER reduction in the in vitro BBB model, and this effect was attenuated by propofol pretreatment. Discussion: The protective effect of propofol on hCMEC/D3 cells' ferroptosis and LDHAlactylation induced by LPS may be an important mechanism for neuroinflammation. Conclusion: Propofol inhibits LPS-induced lactylation, ferroptosis, and release of inflammatory cytokines in hCMEC/D3 cells by downregulating the expression of LDHA.