Astragalus polysaccharides alleviate burn sepsis induced lung injury by suppressing the WTAP/m⁶A/PFKFB3 axis to reduce endothelial pyroptosis

Background Burn sepsis is a life-threatening complication of severe burns, characterized by pulmonary endothelial injury driving acute lung injury (ALI). Pyroptosis and vascular barrier dysfunction are key pathological in this process; however, their underlying mechanisms remain unclear. Astragalus polysaccharides (APS), a natural anti-inflammatory compound, shows protective potential in burn sepsis, but their specific targets in endothelial injury have yet to be elucidated. Methods A murine model of burn sepsis was established by inducing a full-thickness scald injury followed by intradermal LPS injection. Mice were treated with either low- or high-dose APS. Lung histopathology, vascular leakage, and survival rates were assessed. In vitro stimulation of pulmonary microvascular endothelial cells (PMVECs) was performed using serum collected from burn sepsis mice. Pyroptosis markers, barrier function, and gene expression were evaluated. The regulatory role of Wilms’ tumor 1-associated protein (WTAP) /m⁶A/PFKFB3 axis was explored via gene overexpression, methylated RNA immunoprecipitation (MeRIP), RIP, and mRNA stability assays. Results Burn sepsis-induced lung injury was alleviated, and the survival rate of burn septic mice was enhanced following APS treatment. APS suppressed ROS production, NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, and pyroptosis, thereby preserving endothelial barrier integrity both in vivo and in vitro. Mechanistically, APS downregulated WTAP expression, which reduced m⁶A modification and the stability of PFKFB3 mRNA via insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). Furthermore, knockdown of WTAP attenuated pyroptosis and barrier dysfunction in PMVECs, while overexpression of PFKFB3 partially reversed these effects. Conclusion APS protects against burn sepsis-induced lung injury by modulating the WTAP/m⁶A/PFKFB3 axis, thereby alleviating endothelial pyroptosis and preserving vascular integrity. This mechanism underlies the pulmonary vascular protection conferred by APS in burn sepsis.