Discovery of Balasubramide Derivative with Tissue-Specific Anti-Inflammatory Activity Against Acute Lung Injury by Targeting VDAC1

Macrophage-mediated inflammatory responses including pyroptosis are involved in the pathogenesis of sepsis and acute lung injury (ALI), for which there are currently no effective therapeutic treatments. The natural product (+)-Balasubramide is an eight-membered lactam compound extracted from the leaves of the Sri Lanka plant Clausena Indica and has shown anti-inflammatory activities, but its poor pharmacokinetic properties limit its further application for ALI. In this study, a compound (+)3C-20 is discovered with improved both pharmacokinetic properties and anti-inflammatory activity from a series of (+)-Balasubramide derivatives. The compound (+)3C-20 exhibits a markedly enhanced inhibitory effect against LPS-induced expressions of pro-inflammatory factors in mouse macrophages and human PBMCs from ALI patients and shows a preferable lung tissue distribution in mice. (+)3C-20 remarkably attenuates LPS-induced ALI through lung tissue-specific anti-inflammatory actions. Mechanistically, a chemical proteomics study shows that (+)3C-20 directly binds to mitochondrial VDAC1 and inhibits VDAC1 oligomerization to block mtDNA release, further preventing NLRP3 inflammasome activation. These findings identify (+)3C-20 as a novel VDAC1 inhibitor with promising therapeutic potential for ALI associated with inflammation.