{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFSF12, also known as TWEAK, is a multifunctional cytokine that primarily signals through its receptor Fn14, and in certain contexts engages alternative receptors such as CD163. In several studies, TWEAK has been shown to modulate cell fate by provoking both pro‐survival and cell death responses. Depending on the cellular milieu, activation of the TWEAK/Fn14 axis can lead to rapid lysosomal degradation of key survival regulators, promote autocrine TNFα production and subsequent assembly of death‐inducing complexes, and trigger caspase‐dependent apoptosis or cathepsin‐B–mediated necrosis. These cell death–promoting functions are further influenced by factors including cIAP1, TRAF2, and deubiquitinases, underscoring a finely balanced regulatory mechanism that is critical for determining cell survival versus apoptosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in cell death, TWEAK robustly influences cellular proliferation, migration, and tissue remodeling – processes that are particularly relevant to tumor biology and repair/regeneration. Studies in glioma, breast, ovarian, and other tumor models have revealed that TWEAK/Fn14 signaling enhances cell motility and invasive behavior through activation of Rac1 and NF‑κB pathways, establishes positive feedback loops to sustain receptor expression, and synergizes with other pro‐oncogenic signals to promote angiogenesis and matrix remodeling. Similarly, in mesenchymal progenitors and myoblasts, TWEAK fosters proliferation while inhibiting terminal differentiation, suggesting its crucial role in both pathological transformation and regenerative processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTWEAK also plays a pivotal role in orchestrating inflammatory responses and mediating tissue injury and repair across diverse organ systems. In endothelial cells, renal tubular epithelia, and synovial fibroblasts, engagement of Fn14 by TWEAK triggers canonical and noncanonical NF‑κB activation leading to the induction of chemokines, adhesion molecules, and other pro‐inflammatory mediators. This inflammatory signaling contributes to the pathogenesis of conditions such as lupus nephritis, rheumatoid arthritis, inflammatory bowel disease, and atherosclerosis, while also impacting vascular and renal injury. In these settings, TWEAK-induced cytokine production not only recruits inflammatory cells to sites of tissue damage but may also serve as a target for therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct cellular effects, TWEAK is emerging as a potential biomarker and modulator in metabolic and reproductive contexts. Altered circulating levels of its soluble form—and changes in its ratio with scavenger molecules like sCD163—have been associated with chronic kidney disease, cardiovascular outcomes, and even aspects of uterine receptivity. Moreover, its processing from a membrane‐bound precursor and distinctive binding kinetics with Fn14 underscore unique regulatory features that may be harnessed for diagnostic or therapeutic purposes in disorders spanning obesity, stroke, and reproductive failure."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "36", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Masafumi Nakayama, Kazumi Ishidoh, Nobuhiko Kayagaki, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Fibroblast growth factor-inducible 14 mediates multiple pathways of TWEAK-induced cell death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.170.1.341"}], "href": "https://doi.org/10.4049/jimmunol.170.1.341"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12496418"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12496418"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Nhan L Tran, Wendy S McDonough, Benjamin A Savitch, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "TWEAK is a novel arthritogenic mediator."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.177.4.2610"}], "href": "https://doi.org/10.4049/jimmunol.177.4.2610"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16888023"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16888023"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Nhan L Tran, Wendy S McDonough, Benjamin A Savitch, et al. 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