{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPCSK6, also known as PACE4, is a calcium‐dependent serine protease that performs critical “pro‐convertase” functions by cleaving and thereby activating key precursor proteins. In the cardiovascular system, PCSK6 directly cleaves and activates corin—a membrane‐bound serine protease that converts pro–atrial natriuretic peptide into its active form—thus regulating sodium homeostasis, blood pressure, and even atrial septation during heart development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of embryonic development and brain lateralization, PCSK6 contributes by processing factors such as Nodal that are essential for establishing left–right asymmetry, with genetic variation in its regulatory regions being linked to handedness and cerebral structural asymmetries. This role has been highlighted by genome‐wide association studies and functional analyses implicating PCSK6 variants and VNTR polymorphisms in modulating relative hand skill and brain organization."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPCSK6 also modulates the extracellular milieu by processing transforming growth factor–β (TGFβ)–related molecules and by facilitating activation of metalloproteinases. Through its binding to heparin and interaction with extracellular matrix components, it influences tissue remodelling processes such as the activation of aggrecanases in cartilage degradation, as well as responses in atherosclerotic lesions where oxidized lipids up‐regulate PCSK6 activity leading to increased matrix metalloproteinase‐9 activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn numerous cancers, including prostate, ovarian, and breast malignancies as well as melanoma, PCSK6 has emerged as a key modulator of tumor aggressiveness. Its activity not only facilitates the activation of growth factors and metalloproteinases but also, through alternative splicing events that generate oncogenic isoforms (such as PACE4‑altCT), contributes to enhanced cell proliferation, migration, and resistance to apoptosis. Moreover, regulation by factors such as the E2F transcription family and microRNAs further delineates its role in neoplastic progression and positions PCSK6 as a promising therapeutic target and potential biomarker in oncology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in development and cancer, PCSK6 is implicated in inflammatory and degenerative diseases. In rheumatoid arthritis, for example, PCSK6 modulates the behavior of synovial fibroblasts, while in idiopathic pulmonary fibrosis, genetic variants associate with poorer survival outcomes. Furthermore, in Alzheimer’s disease, PCSK6 has been shown to activate membrane‐type 5 matrix metalloproteinase (MT5‐MMP), thereby promoting amyloidogenic processes. Such findings underscore its involvement in diverse inflammatory and stress‐related responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn reproductive physiology, PCSK6 is highly expressed in the placenta and ovarian granulosa cells, where it plays roles in trophoblast differentiation and the regulation of reproductive hormone processing. Epigenetic mechanisms also contribute to its altered expression in these tissues, with implications for conditions such as pre‐eclampsia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}, {"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLastly, expression studies in the nervous system have revealed that PCSK6 and related proprotein convertases are present in the retina and the optic nerve head, suggesting additional roles in neuronal maintenance and function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shenghan Chen, Pengxiu Cao, Ningzheng Dong, et al. 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