Dickkopf-3 (DKK3) in cardiovascular diseases: from a stress-responsive biomarker to a potential therapeutic target

Dickkopf-3 (DKK3) is a secreted glycoprotein that functions as a context-dependent modulator of the Wnt/β-catenin and transforming growth factor-beta (TGF-β) signaling pathways. Originally studied in development and cancer, DKK3 has recently emerged as a key stress-responsive factor. It is released by epithelial and other cell types under pathological strain and actively participates in fibrotic, inflammatory, and remodeling processes across various organ systems. In cardiovascular medicine, DKK3 is gaining recognition not only as a promising biomarker for renal and vascular injury-conditions closely intertwined with cardiovascular outcomes-but also as a direct mediator in the pathogenesis of specific cardiovascular conditions such as abdominal aortic aneurysm (AAA) and heart failure. This review synthesizes current knowledge on DKK3, beginning with its fundamental biology and established roles in renal, pulmonary, and dermal fibrosis, which provide crucial mechanistic parallels. We then focus on the evolving evidence of DKK3's involvement in cardiovascular diseases, critically evaluating its biomarker potential for risk stratification in conditions like diabetic kidney disease and its direct pathophysiological roles in vascular smooth muscle cell phenotype switching, myocardial remodeling, and aneurysm formation. We delve into specific molecular mechanisms, including interactions with the ATF6-TGFβ3-Smad2/3 axis and low-density lipoprotein receptor-related protein 1 (LRP1), as revealed by preclinical models. Finally, we explore the therapeutic implications of targeting the DKK3 axis, discuss the challenges posed by its context-dependent dual roles, and outline future research directions necessary to translate these discoveries into clinical applications for cardiovascular patients.