{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNDRG4 is a member of the N‐myc downstream–regulated gene family that exhibits a distinct tissue‐specific expression pattern. Early molecular studies demonstrated that, unlike its more ubiquitously expressed paralogs, NDRG4 expression is largely restricted to the brain and heart, suggesting specialized functions in neural and cardiac physiology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCardiac genome‐wide studies have implicated NDRG4 in myocardial electrical properties. Variants near the NDRG4 genomic region have been associated with QT interval duration—a critical factor in myocardial repolarization—and mutations in NDRG4 have been shown to impair cardiac myocyte proliferation, suggesting a role in the development of congenital heart defects such as pulmonary atresia with ventricular septal defect and tetralogy of Fallot."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the central nervous system, NDRG4 plays key roles in neuronal differentiation and cell survival. Functional studies in astrocytes and glioblastoma models reveal that NDRG4 is essential for cell cycle progression—its depletion induces G₁ arrest followed by apoptotic cell death mediated through p53 pathways. Reduced NDRG4 expression has been observed in malignant gliomas and aggressive meningiomas, where its low levels correlate with impaired cellular viability and poor clinical outcome. Reviews in this area further support a tumor‐suppressive function for NDRG4 in neural tumors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn several non‐central nervous system cancers, including colorectal, gastric, pancreatic, and adrenocortical carcinomas, NDRG4 frequently acts as a tumor suppressor. Studies have revealed that epigenetic silencing through promoter hypermethylation or downregulation of NDRG4 not only correlates with increased tumor aggressiveness but also serves as a promising diagnostic and prognostic biomarker. For instance, reduced NDRG4 expression in colorectal cancer is associated with adverse clinical outcomes and can even modulate the prognostic impact of obesity, while in gastric and pancreatic cancers, re‐expression of NDRG4 inhibits cell proliferation and metastatic traits. Similar prognostic significance has been found in adrenocortical carcinoma, where high NDRG4 levels identify a more favorable survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA novel homozygous mutation in NDRG4 has also been identified as a putative causative variant in infantile myofibromatosis, indicating that proper NDRG4 function is critical for normal cellular proliferation beyond oncogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence further extends the importance of NDRG4 to neuroprotection and reproductive biology. In an Alzheimer’s disease cell model, NDRG4 overexpression mitigates amyloid beta–induced apoptosis and oxidative stress via upregulation of BDNF and subsequent activation of the PI3K/AKT and MEK/ERK signaling cascades. Moreover, in the uterus, estrogen induces NDRG4 expression, which is critical for decidualization and embryo implantation; reduced levels of NDRG4 in human villus tissues have been linked to recurrent miscarriage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, studies in the enteric nervous system reveal that loss of NDRG4 influences the intestinal microenvironment. Knockout models indicate that the absence of NDRG4 alters the secretome of enteric neurons, leading to increased levels of extracellular matrix modulators such as Nidogen-1 and Fibulin-2; these changes enhance the migration capacity of colorectal cancer cells and contribute to increased adenoma formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xianghu Qu, Yun Zhai, Handong Wei, et al. 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