{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNerve growth factor (NGF) is a quintessential neurotrophin that orchestrates neuronal development, survival and apoptosis by engaging its high‐affinity receptor TrkA and the low‐affinity receptor p75NTR. Structural studies have revealed that NGF functions as a homodimer, wherein an asymmetric interaction with p75NTR—and its modulation by co‐receptors such as sortilin and p62—directs either trophic support or pro‐apoptotic signals when bound to the precursor proNGF. These mechanisms underpin diverse cellular outcomes including neuronal survival, differentiation, and programmed cell death."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNGF critically modulates nociceptive function by sensitizing peripheral sensory neurons. Through activation of TrkA‐dependent signaling—such as the PI3 kinase/Src pathway that phosphorylates TRPV1 channels—it enhances the responsiveness of nociceptors to noxious stimuli. Conversely, mutations in NGF or its gene (as observed in hereditary sensory and autonomic neuropathies) lead to loss of pain perception and impair the hedonic coding of gentle touch, underscoring its essential role in pain modulation and afferent sensory processing."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in sensory processing, NGF exerts potent neurotrophic effects that are vital for neuronal rescue and plasticity. Preclinical models demonstrate that NGF delivery can largely reverse Alzheimer‐like neurodegeneration, with alterations in NGF signaling contributing to deficits in hippocampal function after traumatic brain injury. Such dysregulation of the NGF pathway is linked to cognitive impairment in several neurodegenerative and neuropsychiatric disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classic roles in the nervous system, NGF is an important mediator of neuro‐immune and inflammatory responses in nonneuronal tissues. Epithelial and immune cells—including eosinophils and synovial cells—synthesize and secrete NGF in conditions such as allergic asthma, atopic dermatitis, psoriasis, and even intervertebral disc degeneration. Local NGF production in these settings contributes to neurite outgrowth, tissue remodeling and altered cytokine profiles, thereby linking NGF to both nociceptive sensitization and the modulation of inflammatory microenvironments."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant NGF signaling is also increasingly recognized in the oncogenic process and in various endocrine and psychiatric conditions. In cancer, NGF supports tumor cell survival, proliferation, angiogenesis, and perineural invasion—findings reported in breast, melanoma, prostate, and pancreatic carcinomas. Moreover, dysregulated NGF levels have been associated with neuropsychiatric disorders such as schizophrenia, depression, and attention‐deficit/hyperactivity disorder, as well as endocrine imbalances including polycystic ovarian syndrome and altered ovarian follicle maturation. Notably, NGF-induced gene products (for example, VGF) further modulate cell cycle and apoptotic pathways, and emerging evidence positions NGF and its signaling components as promising diagnostic biomarkers and therapeutic targets."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the cardiovascular realm, NGF contributes to myocardial repair by stimulating angiogenesis and by promoting cardiomyocyte survival through TrkA-mediated activation of downstream kinases such as Akt and Foxo. 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