{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRRAD, a small Ras‐related GTPase, has emerged as an important regulator of cellular metabolism and tumor progression. In several cancer models, RRAD is functionally linked to the control of glycolysis and energy homeostasis. For instance, in lung cancer cells, p53‐dependent induction of RRAD under hypoxic conditions represses glycolysis by inhibiting GLUT1 translocation, while RRAD also impairs the NF‑κB pathway to counter the Warburg effect. In contrast, oncogenic Ras signaling can lead to promoter hypermethylation and silencing of RRAD in ovarian cancer, and its inactivation in nasopharyngeal carcinoma is associated with enhanced cell proliferation and migration. Moreover, in glioblastoma RRAD interacts with EGFR and endosomal proteins to enhance STAT3 activation and cancer stem cell characteristics, whereas in hepatocellular carcinoma its down‐regulation correlates with increased glycolytic activity and a more invasive phenotype. Notably, in gastrointestinal malignancies such as gastric and colorectal cancer, elevated RRAD expression has been observed, and targeting RRAD reduces tumor cell proliferation and invasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cardiac tissues, RRAD is highly expressed and modulates key aspects of excitation–contraction coupling. Studies have demonstrated that RRAD is involved in the regulation of L‑type Ca²⁺ channel activity, with its modulation significantly affecting cardiac contractility and electrical stability. Experimental evidence indicates that RRAD is associated with cardiac hypertrophy and arrhythmias, and reconstitution of the β‑adrenergic–Ca²⁺ channel cascade shows that RRAD is indispensable for the full response to sympathetic stimulation. Furthermore, RRAD’s expression in both heart and skeletal muscle underlines its role in the broader cardiometabolic regulatory network, while its unique conformational features, as revealed by structural studies, provide insights into its inhibitory actions on ion channel function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cancer and cardiac physiology, RRAD is implicated in a variety of other cellular processes. In neuromuscular contexts, oxidative stress—as seen in amyotrophic lateral sclerosis—leads to early up‑regulation of RRAD, which may serve as a negative feedback mechanism to mitigate reactive oxygen species. RRAD also emerges as a universal marker of cellular senescence, where its elevated expression appears to counteract senescence‐associated oxidative damage. At the cell cycle level, RRAD can promote proliferation by binding to and sequestering tumor‐suppressive factors such as GCIP, while in the nucleus it interacts with the NF‑κB p65 subunit, impairing its DNA binding and downstream gene transcription. Elevated RRAD levels have been linked to chemoresistance in leukemia, and its promoter hypermethylation has been observed in esophageal cancer, underscoring its diverse epigenetic regulation. Comprehensive reviews highlight the dualistic nature of RRAD—acting as either a tumor suppressor or oncogene depending on the cellular context—and genetic analyses even suggest its possible involvement in inherited cardiac arrhythmia syndromes and vascular pathologies. Finally, the crystallographic elucidation of the RRAD GTPase domain has provided molecular insights that may inform future therapeutic strategies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Cen Zhang, Juan Liu, Rui Wu, et al. 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