{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nDipeptidyl peptidase III (DPP3) is a ubiquitous zinc‐dependent metalloexopeptidase that catalyzes the sequential removal of dipeptides from the N‐terminus of oligopeptides. Structural and biochemical studies have revealed that DPP3 efficiently degrades several bioactive peptides—including opioid peptides such as enkephalins and tynorphin, as well as peptides involved in the renin–angiotensin system (e.g., angiotensin‐(1–7))—thereby modulating nociceptive signals and cardiovascular homeostasis. Detailed crystallographic analyses, mutagenesis experiments (highlighting the role of key residues such as Tyr318), and molecular dynamics simulations have provided important insights into its active‐site architecture, substrate recognition, and metal–ion coordination dynamics."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n \nDPP3 also plays important non‐catalytic roles in regulating cellular homeostasis. Notably, it can modulate the cellular oxidative stress response by binding to the ubiquitin ligase KEAP1 via an ETGE motif and displacing NRF2, thereby promoting the transcription of cytoprotective genes. In addition, reports suggest that DPP3 influences signal transduction processes such as GPCR‐mediated Ca2+ regulation and intracellular protein turnover, which further supports its role as a regulator in diverse cellular pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "13"}]}, {"type": "t", "text": "\n \nIn the context of cancer and other diseases, aberrant DPP3 expression has been reported in a variety of malignancies—including ovarian, colorectal, glioblastoma, esophageal, and breast cancers—with elevated levels being associated with increased tumor aggressiveness, enhanced cell proliferation and migration, resistance to apoptosis, and poor patient prognosis. Mechanistic studies indicate that DPP3 may promote oncogenic signaling (for example, via downstream targets such as CDK1 or through modulation of the Keap1–NRF2 axis) and can also affect immune recognition by regulating the expression of molecules like MICB, thereby contributing to immune escape."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "21"}]}, {"type": "t", "text": "\n \nBeyond its roles in peptide processing and oncogenesis, circulating and tissue DPP3 levels have emerged as promising biomarkers in several acute and chronic conditions. Elevated DPP3 in plasma has been linked to myocardial depression in cardiogenic shock, hemodynamic instability in severe burns, and has recently been proposed as a prognostic indicator in acute coronary syndromes, delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage, and even COVID-19 severity. In bone metabolism, for instance, reduced DPP3 activity has been associated with increased osteoclast activity and bone fragility in postmenopausal osteoporosis, highlighting its multifaceted clinical relevance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Gustavo A Bezerra, Elena Dobrovetsky, Roland Viertlmayr, et al. 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