PCSK6 (proprotein convertase subtilisin/kexin type 6) is a secreted serine endoprotease that cleaves various proproteins at paired basic amino acids following the RXXX[KR]R consensus motif 1. It is expressed across most major organs with tissue-restricted distribution in both neuroendocrine and non-neuroendocrine tissues, functioning primarily in the constitutive secretory pathway 1. PCSK6 processes multiple substrates including growth factors, signaling molecules, peptide hormones, and adhesion proteins, with particular importance in extracellular matrix remodeling 1. In developmental contexts, PCSK6 is essential for embryonic development and body axis specification through the NODAL pathway, influencing human lateralization and handedness 2. Within the cardiovascular system, PCSK6 modulates heart formation, lipoprotein metabolism, and vascular remodeling 1. Dysregulated PCSK6 expression associates with atrial septal defects through interactions with Tbx5 and Osr1 in the second heart field 3, and with atherosclerotic plaque instability where it localizes to smooth muscle cells and the fibrous cap 4. Clinically, PCSK6 functions as a novel target antigen in membranous nephropathy, an autoimmune glomerulonephritis causing nephrotic syndrome 56. Additionally, PCSK6 genetic variants associate with idiopathic pulmonary fibrosis progression and survival outcomes 7, with elevated protein expression linked to reduced transplantation-free survival.