{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTumor necrosis factor (TNF) is a multifunctional cytokine that orchestrates cell fate decisions by triggering diverse modes of cell death. TNF can promote both apoptosis and necroptosis – for example, in combination with Smac mimetics it drives the formation of complexes containing RIPK1, RIP3, and caspase‑8, initiating programmed necrosis – and it can induce sustained JNK activation through reactive oxygen species (ROS)–mediated inhibition of phosphatases, thus further propagating death signals."}, {"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": "\nIn addition to its role in cell death, TNF is a central mediator of inflammatory and immune responses. It robustly activates NF‑κB and other transcriptional programs through dynamic protein interaction networks, thereby modulating the expression of a wide array of immune response genes. TNF also participates in autocrine and paracrine amplification loops – including those involving interferon‑β – which contribute to the persistence of inflammation in autoimmune disorders, psoriasis, and conditions associated with neuropathic pain."}, {"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": "\nTNF further plays a critical role in metabolic regulation and endocrine function. Elevated TNF levels can impair insulin signaling by reducing the expression of key mediators such as adiponectin and by disrupting insulin receptor substrate phosphorylation; such effects contribute to insulin resistance in adipose tissue and have been implicated in the pathogenesis of nonalcoholic steatohepatitis, gestational insulin resistance, and obesity‐associated metabolic derangements."}, {"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": "\nTNF’s influence extends to the central nervous system and cancer biology. In neural contexts, TNF modulates synaptic activity by altering the expression of excitatory (e.g., AMPA and NMDA) and inhibitory (GABA) receptors, thereby linking neuroinflammation with excitotoxicity, seizure propensity, and neurodegeneration. In cancer, TNF-dependent NF‑κB activation can stabilize pro-metastatic regulators such as Snail, thus promoting tumor cell migration and invasiveness. Moreover, dysregulated TNF signaling underlies adverse drug reactions, influences autophagy and endoplasmic reticulum stress responses, and modulates epithelial barrier integrity via upregulation of myosin light chain kinase. In parallel, TNF production and function are tightly regulated by both intracellular mechanisms – including posttranslational modifications and interactions with inhibitor of apoptosis proteins – and extracellular factors such as noncoding RNAs and microbial metabolites (for instance, bacterial histamine acting via H₂ receptors), which open promising therapeutic avenues in autoimmune diseases, inflammatory disorders, and malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sudan He, Lai Wang, Lin Miao, et al. 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