{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nADORA3 plays a pivotal role in immune regulation and inflammation. In neutrophils, for example, extracellular ATP released at the leading edge is rapidly metabolized to adenosine, which then activates ADORA3 locally to enhance chemotactic migration. In neonatal and activated lymphoid cells, heightened ADORA3 sensitivity modulates Toll‐like receptor–mediated responses by preferentially inhibiting pro‐inflammatory TNF‑α production while sparing immunoregulatory IL‑6 synthesis. In addition, ADORA3 expressed on mast cells, monocytes and macrophages is involved in controlling tissue factor expression, matrix metalloproteinase release, and the migratory capacity of endothelial progenitor cells – all of which underscore its central function in coordinating inflammation and immune cell trafficking."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer biology, ADORA3 exerts context‐dependent actions that include the inhibition of tumor cell proliferation through down‐regulation of NF‑κB and cyclin D1, as well as the induction of apoptosis in several malignancies such as hepatocellular carcinoma, breast, prostate and bladder cancers. In colorectal adenocarcinomas and other solid tumors, activation of ADORA3 has been shown to mediate tonic proliferative signals that can be modulated by endogenous adenosine, while its engagement may also attenuate angiogenic factor secretion in melanoma models. These findings collectively position ADORA3 as a promising therapeutic target in oncology, with its activation or blockade able to influence tumor growth, metastatic potential and the surrounding microenvironment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructure–function studies have revealed critical insights into the molecular underpinnings of ADORA3 signaling. Site‐directed mutagenesis and radioligand binding experiments have identified key amino acid residues essential for ligand recognition, receptor activation and allosteric modulation, as well as demonstrated the existence of highly cooperative homodimer interactions that affect agonist dissociation kinetics. Furthermore, investigations into receptor desensitization, internalization and recycling in cellular models – alongside the discovery of novel high‐affinity ligands such as N6‑methyladenosine – have advanced our understanding of ADORA3’s dynamic signaling properties and informed the design of selective pharmacological modulators."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in immune modulation and tumor biology, ADORA3 has emerged as a promising target for therapeutic intervention. In cardiac myocytes, ADORA3 activation triggers protective signaling cascades involving RhoA and phospholipase D that mitigate ischemia‐induced injury, while genetic variants in the ADORA3 gene have been correlated with differences in infarct size. These findings, together with evidence for the analgesic potential of ADORA3 agonists, support the development of ADORA3‐targeted drugs across a spectrum of clinical indications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Igor Feoktistov, Sergey Ryzhov, Anna E Goldstein, et al. 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