BAM15 treatment mitigates lipopolysaccharide-induced acute lung injury by preserving mitochondrial dynamic equilibrium and modulating inflammatory responses via the cGAS–STING signalling pathway

Acute lung injury (ALI) is a life-threatening condition that is often induced by endotoxins and leads to severe inflammation and mitochondrial dysfunction. In this study, we investigated the protective effects of BAM15 {C ₁₆ H ₁₀ F ₂ N ₆ O; also known as N5,N6-bis(2-fluorophenyl)-[1, 2, 5]oxadiazolo[3,4-b]pyrazine-5,6-diamine}, a mitochondrial uncoupler, in lipopolysaccharide (LPS)-induced ALI, focussing on its role in the regulation of mitochondrial dynamics and immune responses. Using a mouse model of LPS-induced ALI, we assessed mitochondrial dynamics by imaging and biochemical assays, and analysed cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway activation using western blotting and immunofluorescence. We found that BAM15 treatment resulted in a significant reduction in mortality and attenuated lung inflammation, oxidative stress and autophagy. Moreover, BAM15 contributes to the maintenance of mitochondrial dynamics by promoting mitochondrial fusion and inhibiting fission whilst downregulating cGAS–STING activation, thereby rectifying delayed neutrophil apoptosis and attenuating inflammation. BAM15 protects against LPS-induced ALI by maintaining mitochondrial homeostasis, reducing the generation of mitochondrial reactive oxygen species, and limiting excessive autophagy. It also reduces mitochondrial DNA release and prevents excessive cGAS–STING activation. On the basis of these findings, we propose that BAM15 could represent a promising therapeutic candidate for the treatment of LPS-induced ALI.