{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nVGF is emerging as a multifaceted neuropeptide precursor whose products play critical roles in neuroprotection and synaptic plasticity. In Alzheimer’s disease models, for example, VGF was identified as a high‐confidence master regulator, and its overexpression partially rescued beta‐amyloid–induced memory impairments and neuropathology. In amyotrophic lateral sclerosis (ALS), specific VGF‐derived peptides in cerebrospinal fluid correlate with disease progression and motorneuron survival, while experimental enhancement of VGF expression protects neurons against excitotoxic injury. Moreover, in the context of Alzheimer’s pathology even on an APOE E4 background, high VGF expression appears protective and is associated with improved cognitive outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn mood and psychiatric disorders, changes in VGF expression have been repeatedly implicated. Reduced VGF mRNA levels in the brain and peripheral blood correlate with major depression, whereas its modulation by antidepressant treatments and mood stabilizers like LiCl suggests that VGF is integral to the molecular mechanisms underlying mood regulation. Furthermore, knockdown studies indicate that reduced VGF may contribute to the pathophysiology of major mental illnesses, and differential serum VGF levels have even shown potential as biomarkers to distinguish between major depressive disorder and bipolar depression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nVGF also plays a significant role in metabolic and endocrine regulation. The VGF precursor is processed into various peptides that help govern food intake, energy balance, and glucose homeostasis. Studies in both humans and animal models have revealed altered VGF peptide levels in obesity and type 2 diabetes, with changes in plasma and adipose tissue correlating with defects in metabolic responses. Moreover, VGF‐derived peptides such as TLQP, NAPP, and QQET, as well as the NERP peptides, modulate insulin secretion and adipocyte function, and dysregulation of VGF expression has been linked to abnormal energy expenditure and even cancer progression in pancreatic neuroendocrine neoplasms and lung neoplasms, where increased VGF expression is associated with poor prognosis and drug resistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in the central nervous system and metabolism, VGF is also expressed in peripheral immune cells. Expression levels in T cells not only increase with age but are also correlated with T cell survival and cytokine secretion. These findings suggest that VGF contributes to the regulation of immune cell function and may serve as a marker of immunosenescence and metabolic alterations in aging."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, VGF gene expression is tightly regulated. Its transcriptional control involves neurotrophin-inducible mechanisms and repressive elements such as NRSE binding by NRSF, which modulate VGF expression in a cell type–specific manner. Structural analyses of VGF-derived peptides like AQEE-30 have revealed stable α-helical conformations with amphiphilic surfaces, properties that likely facilitate their interaction with cell membranes and receptors to execute diverse biological functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA number of additional studies provide broader context for these findings. While challenges in biomarker identification for ALS have been noted and genetic association studies in psychiatric disorders have yielded mixed results regarding VGF, fundamental reports confirm its expression in mammalian neurons and endocrine cells. Other investigations have examined the role of epigenetic modifications in various malignancies or the genetic underpinnings of eating disorders in which VGF variants may contribute. These complementary works underscore the importance of further elucidating VGF’s multifaceted functions across physiological systems."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Noam D Beckmann, Wei-Jye Lin, Minghui Wang, et al. 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