PCSK6 in Pathophysiology and Its Potential Involvement in Pulmonary Fibrosis

Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a proteolytic enzyme that may act on a broad spectrum of substrates, including growth factors, extracellular proteases, adhesion molecules, protease activated receptor 1, the prorenin receptor, and Corin. As a consequence of its broad-spectrum substrate activity, PCSK6 is implicated in a wide range of pathophysiological processes such as cardiovascular disease, neurological disorders, arthritis and cancer. Of special interest, PCSK6 has recently been shown to be highly expressed in patients with idiopathic pulmonary fibrosis (IPF) and PCSK6 has been associated with reduced survival of IPF patients, linking PCSK6 to pulmonary fibrosis for the first time. Of note however, PCSK6 levels in plasma were not associated with respiratory outcomes in IPF patients and higher PCSK6 levels were even associated with a lower hazard of 10% FVC decline in non-IPF ILD patients. In this review, we summarize the molecular biology of PCSK6, including its structural features and its major (potential) substrates, and outline its pathophysiological roles across various diseases. Furthermore, we propose and discuss the potential involvement of PCSK6 in pulmonary fibrosis to guide future research.