Although we have gained much knowledge about the signal transduction pathways at the molecular level in physiological and pathophysiological conditions in the last decades, it is still a major challenge to identify a molecular therapeutic target in a given disease. We describe a signaling pathway-oriented global transcriptional analysis, which identified JNK, a stress-activated protein kinase, as a proximal signaling molecule in the pathogenesis of abdominal aortic aneurysm (AAA). AAA is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. AAA has long been considered an irreversible destructive process and regression of AAA by non-surgical methods has not been expected. We show that JNK programs a gene expression pattern that cooperatively enhances the degradation of the extracellular matrix, while suppressing biosynthetic enzymes of the extracellular matrix. Selective inhibition of JNK in vivo not only prevented the development of AAA but also caused regression of established AAA in mice. These results revealed that JNK promotes abnormal ECM metabolism in AAA and represents a novel "druggable" therapeutic target for AAA.