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

Abstract 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.