Ccn4, also known as WNT1-Inducible Signaling Pathway Protein 1 (WISP1), is a highly conserved, secreted cysteine-rich matricellular protein located on chromosome 8q24.1-8q24.3 [2]. It is involved in multiple cellular mechanisms such as cell proliferation, migration, invasion, angiogenesis, wound healing, repair, and apoptosis [1]. Ccn4 is a downstream target of β-catenin and has an intricate relationship with pathways like protein kinase B (Akt), mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and mammalian forkhead transcription factors (FoxOs) [4]. It is of great biological importance as its aberrant expression is associated with numerous disease pathologies including cancer, fibrosis, metabolic and inflammatory disorders [1].

In a high-fat-fed ApoE-/-mouse model, Ccn4 overexpression led to reduced occlusion of the brachiocephalic artery with less apoptosis, fewer macrophages, and attenuated lipid core size, while Ccn4 deficiency resulted in increased apoptosis and occlusion as well as increased plaque in the aortic root [3]. In another study using apolipoprotein-E knockout (ApoE-/ -) mice fed a high-fat diet and infused with Angiotensin II, deletion of Ccn4 significantly reduced the number of ruptured aortae, aortic area, and aneurysm grade score, along with decreased macrophage infiltration and cell apoptosis [5].

In conclusion, Ccn4 plays essential roles in cell survival, migration, and apoptosis, which are crucial in various disease conditions. The use of gene knockout mouse models, such as ApoE-/-mice with Ccn4 deletion, has revealed its significant impact on atherosclerosis and aneurysm progression, providing potential therapeutic implications for these diseases.