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 (MYH9ECKD) 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. MYH9ECKD 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.