Human Epididymis Protein 4 in Cardiovascular Disease　― A Fibrosis-Driven Mediator of Tissue Remodeling and Inter-Organ Communication ―

Abstract

Human epididymis protein 4 (HE4), originally identified as a tumor biomarker, has emerged as a regulator of tissue remodeling, with roles that extend beyond oncology. Recent findings suggest that HE4 is involved in extracellular matrix turnover, immune system modulation, and maintenance of epithelial balance, indicating its complex role in fibrosis and tissue remodeling. In cardiovascular diseases, the circulating HE4 level is consistently associated with disease severity, myocardial fibrosis, and adverse clinical outcomes in conditions such as heart failure, aortic stenosis, and ischemic heart disease, suggesting its role as a marker of fibrosis-driven remodeling in diverse cardiovascular conditions. Mechanistically, HE4 influences fibrosis via protease inhibition, fibroblast activation, and immune signaling pathways, and may function as a mediator of inter-organ communication. In particular, its strong association with renal dysfunction and expression in injured kidney tissues supports its role in cardiorenal interactions. Recent findings suggest that HE4 plays a role in systemic remodeling processes that extend beyond heart function, including those associated with pulmonary vascular disease. Collectively, these insights propose a conceptual framework in which HE4 acts as a context-dependent regulator of tissue remodeling, integrating structural, immune, and inter-organ communication pathways. This perspective positions HE4 as a biomarker and a mechanistically relevant mediator of disease progression, with potential implications for risk stratification and therapeutic targeting in cardiovascular disease.