Formononetin protects against sepsis-induced lung injury by directly inhibiting receptor for advanced glycation end products signaling pathway

Excessive inflammatory response is the pathological basis of septic lung injury. Although formononetin (FMN) exerts an anti-inflammatory activity, its effect on sepsis-induced lung injury and the associated mechanisms remain unknown. Hence, in this study, we explored how FMN affected septic lung injury and the underlying mechanisms. We constructed mouse model of sepsis-induced lung injury through cecal ligation and puncture (CLP) in vivo , and utilized lipopolysaccharide (LPS) to stimulate RAW 264.7 cells for simulating inflammatory environment during septic condition in vitro . Specifically, FMN treatment significantly suppressed the generation of inflammatory factors, such as TNF-α, IL-1β, and IL-6. In addition, FMN treatment alleviated lung pathological damage, inhibited apoptosis, and improved lung barrier dysfunction. Moreover, FMN administration markedly reduced the protein level of RAGE, and inhibited the phosphorylation levels of NF-κB (p65), IκBα, JNK, ERK, and p38. Surface plasmon resonance imaging (SPRi) and molecular docking revealed that FMN could bind to RAGE protein and form a stable connection with RAGE. Meanwhile, silencing RAGE significantly abolished FMN’s activity against inflammation in RAW 264.7 cells. FMN combined with RAGE inhibitor treatment did not further increase FMN’s protective effect against septic lung injury mice. In conclusion, FMN protects against septic lung injury through directly suppressing RAGE signaling pathway. These results suggest that FMN exhibits potential as a viable drug candidate for treating septic lung injury.