Phillyrin promotes flap survival by mitigating pyroptosis through the TLR4/NF-κB/NLRP3 signaling pathway

Flap transplantation is a widely used for wound reconstruction but continues to carry a substantial risk of postoperative necrosis. We evaluated the therapeutic effect of phillyrin for improving flap survival and elucidated its underlying pharmacological mechanisms.

In vivo, a McFarlane flap model was established on the dorsal skin of rats. Animals were assigned to four groups: control, low-dose (17.5 mg/kg/day, intraperitoneal [i.p.]), medium-dose (35 mg/kg/day, i.p.), and high-dose (70 mg/kg/day, i.p.) phillyrin. At 7 days postoperatively, we evaluated flap survival, blood perfusion, oxidative stress, cytokine expression, toll-like receptor 4/nuclear factor κB/NOD-like receptor protein 3 (TLR4/NF-κB/NLRP3) axis activity, and pyroptosis. In vitro, human umbilical vein endothelial cells were treated with hypoxia/reoxygenation or lipopolysaccharide/nigericin models, to investigate the protective effects of phillyrin against inflammation-related pyroptotic injury.

Phillyrin improved flap survival, significantly enhanced local blood perfusion, reduced neutrophil infiltration, and mitigated oxidative stress. Its mechanism of action is closely associated with the inhibition of the TLR4/NF-κB/NLRP3 axis: phillyrin significantly downregulated pathway activity, reduced cytokines secretion, and decreased the expression of pyroptosis-related effector proteins. In vitro, phillyrin demonstrated anti-inflammatory and anti-pyroptotic cytoprotective effects in H/R and inflammatory injury models by modulating the TLR4/NF-κB/NLRP3 axis.

Phillyrin improves flap survival by inhibiting the TLR4/NF-κB/NLRP3 signaling pathway, suppressing excessive inflammation and alleviating ischemia-reperfusion injury.