Ruscogenin attenuates sepsis-induced multiple organ injury by inhibiting NMMHC IIA

Sepsis-induced endothelial dysfunction contributes to systemic inflammation and multiple organ injury. Non-muscle myosin heavy chain IIA (NMMHC IIA) has emerged as a potential therapeutic target for sepsis. However, effective interventions remain limited. This study investigated whether ruscogenin (RUS) alleviates sepsis-induced multiple organ injury by regulating NMMHC IIA. Sepsis was induced in mice via cecal ligation and puncture. Endothelium-specific NMMHC IIA-knockdown ( MYH9 ECKD ) mice were created using the Cre-loxP system. Histopathology, Western blotting, immunofluorescence, Evans blue (EB) leakage, enzyme-linked immunosorbent assay, and biochemical assays were performed to evaluate organ injury, inflammation, and vascular permeability. An in vitro lipopolysaccharide (LPS)-induced endothelial injury model was established in human umbilical vein endothelial cells, and endothelial integrity was evaluated using transendothelial electrical resistance and EB–albumin permeability assays. NMMHC IIA expression markedly increased in multiple organs during sepsis. MYH9 ECKD alleviated sepsis-induced multiple organ injury, including lung, intestine, liver, and kidney damage. RUS markedly improved survival, reduced vascular hyperpermeability, and alleviated inflammatory and organ injury responses in septic mice and LPS-stimulated endothelial cells, which was associated with TLR4/MyD88/NF-κB signaling pathway suppression. However, RUS provided no additional benefit after NMMHC IIA silencing, supporting an endothelial NMMHC IIA-dependent mechanism. Endothelial NMMHC IIA is a key mediator of sepsis-induced multiple organ injury. RUS exerts protective effects against sepsis by targeting NMMHC IIA. These findings provide new insights into the treatment of sepsis-associated multiple organ injuries and warrant further investigation for potential clinical applications.