Cartilage intermediate layer protein (CILP) in cardiac fibrosis: Protective or pathogenic?

Heart failure (HF) is often accompanied by cardiac fibrosis, a pathological process defined by excessive deposition of extracellular matrix (ECM) and predominantly mediated by cardiac fibroblasts. The accumulation of ECM leads to myocardial remodeling and stiffening, impairing cardiac function and exacerbating the risk of cardiac arrhythmia. Cartilage intermediate layer protein (CILP) is a matricellular protein that has recently been associated with cardiac fibrosis and identified in cardiac fibroblasts. While CILP is known to respond to mechanical stress and modulates ECM synthesis in cartilage, its function, regulation, and mechanism of action in cardiac tissue remain poorly understood. Both in cardiac fibroblasts and chondrocytes, the well-known profibrotic transforming growth factor beta (TGF-β) promotes CILP expression. However, the existing literature leads to a contradiction in its function: while some evidence indicates a protective role by inhibiting TGF-β signaling in the heart, others have shown a pathogenic role, where CILP promotes fibrosis. Additionally, studies have reported increased circulating CILP levels in patients with cardiovascular or cardiometabolic disorders, suggesting potential as a biomarker of HF. Nevertheless, these human association data do not clarify whether CILP is protective or pathogenic. This review summarizes the existing knowledge about CILP in cardiac tissue, explores its connections with distinct cardiac fibroblast subpopulations and evaluates its potential as biomarker and therapeutic target in cardiac fibrosis.