{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nDeath receptor 6 (DR6) plays a crucial role in tumor progression by mediating non‐canonical cell death pathways that facilitate metastasis. For instance, DR6 on endothelial cells is activated by interactions with tumor cell–derived signals to induce programmed necrosis (necroptosis), thereby promoting tumor cell extravasation and metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, DR6 is implicated in the regulation of pyroptosis through mechanisms that involve receptor endocytosis and caspase‐8–mediated cleavage of gasdermin family members, processes that can effectively inhibit tumor growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " DR6 has also emerged as a candidate gene in studies mapping host susceptibility to pathogens such as influenza."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, DR6 is a versatile regulator of neuronal health. It acts as a negative regulator of oligodendrocyte maturation, where its elevated expression in immature oligodendrocytes limits myelination."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " DR6 forms part of signaling complexes with p75 neurotrophin receptor that mediate amyloid‐β–induced cortical neuron death, linking its function to the pathogenesis of Alzheimer’s disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, DR6 governs axon degeneration and pruning during development and in response to injury, with studies showing that its loss preserves axons but causes profound alterations in myelin remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": " DR6 also supports blood–brain barrier formation and function, with its dysregulation contributing to barrier breakdown in Alzheimer’s disease models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDR6 further exerts significant immunomodulatory functions. Its expression is tightly regulated in lymphoid cells, and genetic disruption of DR6 leads to enhanced CD4⁺ T cell expansion, skewing toward T helper 2 (Th2) differentiation, and hyperresponsiveness of B cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In models of inflammatory and autoimmune diseases—including allergic airway inflammation, experimental autoimmune encephalomyelitis, and graft‐versus‐host disease—DR6 deficiency is associated with altered cytokine profiles and impaired leukocyte migration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": " A protective role for DR6 has also been demonstrated in ischemia–reperfusion injury, where a p53/miR‑17‑5p/DR6 axis attenuates tubular cell apoptosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", and regulation of autoreactive follicular helper T cells via interactions with syndecan‑1 appears to modulate lupus‐like disease progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Boris Strilic, Lida Yang, Julián Albarrán-Juárez, et al. 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