Human Epididymis Protein 4 (HE4) as a promising biomarker and therapy target in fibrotic diseases: A review

Abstract

The treatment of fibrosis faces a significant challenge due to the lack of effective therapies that can reverse established fibrosis. Early detection is vital for intervention, yet distinguishing fibrosis from normal tissue repair is complex. Human Epididymis Protein 4 (HE4), a traditional tumor marker, has been found to be increased in some non-neoplastic conditions, such as fibrosis related diseases. According to properties analysis, HE4 has been characterized as a highly stable cross-class protease inhibitor, which interacts with key fibrotic proteins (such as MMP2 and PRSS family members) and potentially involves in the progression of fibrosis by inhibiting the enzymatic activity of these proteins. Meanwhile, studies indicated that HE4 may be involved in fibrosis through PI3K/AKT, NF-κB, MAPK, and other signaling pathways. Here we summarized the latest research progress of HE4 in pulmonary fibrosis, renal fibrosis, myocardial fibrosis, liver fibrosis, and autoimmune diseases induced fibrosis. As reported in this review, HE4 was closely related to disease severity and prognosis, and also was a promising prognostic evaluation marker and therapeutic intervention target for fibrotic diseases.