{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProlidase (PEPD) is a widely expressed cytosolic dipeptidase that catalyzes the hydrolysis of dipeptides terminating in proline or hydroxyproline, making it a critical enzyme for collagen turnover and extracellular matrix remodeling. Structural analyses have shed light on its substrate‐binding modes and catalytic mechanisms, while genetic studies of prolidase deficiency reveal that impaired activity leads to multisystem connective tissue disorders characterized by skin lesions, immune dysregulation, and defective wound healing. Moreover, altered prolidase activity has been linked to various musculoskeletal and fibrotic conditions, including osteoarthritis, coronary artery disease, and nonalcoholic fatty liver disease, underscoring its rate‐limiting role in collagen degradation and tissue repair."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical enzymatic function, PEPD serves as a signaling molecule that exerts non‐enzymatic roles. It can act as an extracellular ligand to receptors such as the epidermal growth factor receptor (EGFR) and ErbB2, thereby triggering downstream pathways that promote cellular proliferation, angiogenesis, and survival. In addition, PEPD modulates stress‐responsive processes by influencing hypoxia‐inducible factor‐1α (HIF‑1α)–dependent angiogenic signaling, and it directly interacts with key regulatory proteins like p53 and interferon receptor subunits, thus playing an integral role in tumor suppression and antiviral immune responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in PEPD activity have been associated with a spectrum of pathological states. Changes in serum prolidase levels have been observed in conditions affecting collagen metabolism and oxidative stress—including polycystic ovary syndrome, Helicobacter pylori–induced gastric mucosal damage, hypertension, endometrial and bladder cancers, as well as in uterine fibroids. In cardiovascular pathology, diminished prolidase activity correlates with aortic aneurysm and adverse remodeling in coronary artery disease. Similarly, aberrant prolidase expression is reported in pulmonary, neurological, and rheumatologic conditions such as tuberculosis, joint hypermobility, Behçet’s disease, and even in metabolic disturbances linked to diabetic foot ulcers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nImportantly, targeting PEPD activity holds therapeutic promise. Novel strategies include exploiting its role in prodrug bioactivation in cancer cells as well as modulating its activity to correct aberrant collagen turnover in fibrotic and degenerative diseases. Studies using platelet‐rich plasma to stimulate PEPD have demonstrated enhanced wound healing, while efforts to modulate its cofactor binding and protein folding have opened new avenues for correcting prolidase deficiency. Additionally, emerging evidence suggests that PEPD may contribute to the pathogenesis of type 2 diabetes, and its genetic variability is being explored as a potential biomarker and therapeutic target in metabolic and inflammatory diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Piotr Wilk, Monika Uehlein, Jacqueline Kalms, et al. 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