{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFRSF10A, which encodes the TRAIL receptor 1 (DR4), is a pivotal cell‐surface death receptor that, upon binding to its ligand TRAIL, initiates the extrinsic apoptotic cascade. Its proper function depends not only on sufficient gene and protein expression but also on maintenance of an appropriate level of receptor at the plasma membrane. Multiple studies have shown that mechanisms such as clathrin‐mediated endocytosis, transcriptional regulation (for example via AP‑1 and NF‑κB pathways), and post‐transcriptional modulation (including targeting by microRNAs) critically influence the surface abundance of TNFRSF10A. Loss or intracellular sequestration of DR4 is closely associated with resistance to TRAIL–induced apoptosis in diverse cancer cell types."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in TNFRSF10A expression have been implicated in the pathogenesis and therapeutic resistance of various malignancies—including breast, ovarian, colorectal cancers, and mesothelioma. Epigenetic silencing (for example, by promoter hypermethylation), genetic deletions in the chromosomal region encompassing the TRAIL receptors, and even point mutations can diminish DR4–mediated signaling. Conversely, restoring or enhancing TNFRSF10A expression resensitizes tumor cells to TRAIL–induced apoptosis and may additionally modulate downstream pro‐inflammatory signals (via NF‑κB activation), underscoring its role as a dosage‐dependent tumor suppressor. Moreover, several studies have highlighted that manipulation of TNFRSF10A activity can alter cellular differentiation and immune responses, thereby offering opportunities for targeted anticancer therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to transcriptional and epigenetic control, TNFRSF10A function is modulated by post–translational mechanisms and interactions with diverse cellular factors. Ubiquitin ligases (such as MARCH‐8) regulate DR4 degradation and cell–surface residency, while chemical modifications like S–nitrosylation promote its pro–apoptotic activity. Furthermore, exposure to chemotherapeutic agents (for example, resveratrol, bufalin, azadirone, and alpha–tocopheryl succinate), viral proteins (such as HCMV UL141), and even regulatory long non–coding RNAs can influence TNFRSF10A expression and signaling. These multifaceted regulatory layers underscore the potential for targeting DR4 and its associated networks not only to overcome TRAIL resistance in cancers but also to affect inflammatory processes in other pathological contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "47"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jan Dörr, Ingo Bechmann, Sonia Waiczies, et al. 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