{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNeurotensin (NTS) is an essential gut‐derived peptide that is coexpressed in enteroendocrine cells along with a host of other regulatory hormones – including cholecystokinin, GLP‐1, and secretin – and plays a critical role in nutrient sensing and absorption. In these cells, NTS is not only involved in modulating intestinal secretions and motility but also in promoting lipid absorption and energy homeostasis; elevated levels of its stable precursor have been associated with obesity, diabetes mellitus, and related cardiovascular risk. Moreover, precise intracellular signaling elements—including PKC, protein kinase D, mTOR, and posttranslational modifications – critically modulate NTS release and gene expression, thereby linking gut hormone release to systemic metabolic status."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its pivotal metabolic functions, NTS acts as a potent oncogenic modulator in a wide range of human malignancies. In several tumor types – including those of the pancreas, lung, breast, stomach, liver, and brain as well as in certain hematological malignancies – an autocrine and/or paracrine NTS loop drives tumor cell proliferation, migration, epithelial–mesenchymal transition, angiogenesis, and maintenance of stem‐like properties. These protumorigenic actions are mediated through diverse intracellular cascades such as MAPK/ERK, PKC/PKD, NF‑κB, EGFR/HER, and GSK‑3 pathways, and NTS expression and receptor overexpression have been linked to treatment resistance and poor clinical outcome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the central nervous system and immune compartments, NTS serves additional neuromodulatory and immunoregulatory functions. It exerts a potent excitatory action on dopaminergic neurons—via PKC‐dependent heterologous desensitization of dopamine D2 receptors—and displays direct antimicrobial properties. Increased circulating levels of NTS or its precursor have been implicated in neurodevelopmental disorders such as autism and may contribute to cognitive dysfunction, while in peripheral tissues NTS influences cytokine expression and cellular migration relevant to inflammatory processes and wound healing."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDetailed mechanistic investigations have revealed that NTS receptor activation is followed by rapid internalization and β‐arrestin–mediated trafficking as well as rearrangements in downstream kinase networks—including PKC, PKD, and alterations in GSK‑3 activity—that fine‐tune its diverse cellular effects. Such intricate signaling has spurred the design of novel therapeutic strategies ranging from receptor antagonists and pathway inhibitors to nanoparticle–based delivery systems decorated with multivalent NTS analogs, which collectively aim to counteract NTS‐driven pathophysiology in cancer and metabolic diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "38", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kristoffer L Egerod, Maja S Engelstoft, Kaare V Grunddal, et al. 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