Lactylation of MYH9 and its impact on FOXO3a/Bim signaling in sepsis-induced gut-vascular barrier injury.

The gut-vascular barrier (GVB) is the ultimate defense of the intestine, meticulously regulating the exchange of substances between the intestinal lumen and the circulatory system. Elevated expression of myosin heavy chain 9 (MYH9) has been implicated in blood-brain barrier dysfunction following cerebral ischemic/reperfusion injury and in lung endothelial barrier disruption during acute lung injury. However, the role of MYH9 in GVB dysfunction during sepsis remains unclear. We hypothesized that MYH9 contributes to GVB injury in sepsis. To test this hypothesis, we established a mouse model of sepsis via cecum ligation and perforation (CLP). Mice received an intraperitoneal injection of the MYH9 inhibitor, blebbistatin (5 mg/kg), 1 h before CLP. Furthermore, lipopolysaccharide was used to simulate septic conditions in human umbilical vein endothelial cells. Our results demonstrate that MYH9 is upregulated during sepsis and contributes to GVB injury. Beyond increased transcriptional levels, MYH9 lactylation was also elevated. Silencing MYH9 expression reduced the nuclear translocation of dephosphorylated Forkhead box O3a(FOXO3a). Subsequently, FOXO3a knockdown significantly inhibited downstream pro-apoptotic signaling and enhanced cell viability, confirming the involvement of this pathway. In summary, our study demonstrates that MYH9, stabilized through lactylation modification, activates the FOXO3a/Bcl-2-interacting mediator of cell death (Bim) signaling pathway to induce GVB injury during sepsis.