RRAD, short for Ras-related associated with diabetes, is a member of the Ras-related GTPase superfamily. Primarily a cytosolic protein that activates in the plasma membrane, it is highly expressed in type 2 diabetes patients and serves as a biomarker for congestive heart failure. RRAD is involved in multiple cellular activities such as cell division, motility, apoptosis, and energy metabolism, by modulating tumor-related gene expression and interacting with downstream effectors [1].

In cancer, RRAD shows dual roles. In gastric and colorectal cancer, its inhibition via siRNA/shRNA led to decreased tumor cell proliferation in vitro and in vivo, along with reduced cell invasion, decreased EMT markers, angiogenesis, and associated proteins like VEGF and ANGP2, suggesting it could be a therapeutic target [2]. In papillary thyroid cancer, the NEAT1_2/RRAD/EHF positive feedback loop facilitated aerobic glycolysis [3]. In hepatocellular carcinoma, RRAD suppressed the Warburg effect by downregulating ACTG1, reducing cell proliferation, arresting the cell cycle, and increasing apoptosis [4]. In lung cancer, it inhibited the Warburg effect through negative regulation of the NF-κB signaling [5]. In contrast, in malignant glioblastoma, RRAD promoted EGFR-mediated STAT3 activation and temozolomide resistance [6]. In pancreatic cancer, SETD8 inhibited ferroptosis by inhibiting RRAD expression [7]. In oral squamous cell carcinoma, downregulation of RRAD in the tumor margin enhanced energy metabolism and tumor progression [8]. Also, RRAD was identified as a marker and negative regulator of cellular senescence, with its up-regulation countering cellular senescence by reducing reactive oxygen species levels [9].

In conclusion, RRAD is a multifunctional gene involved in various biological processes and diseases, especially cancer. Its dual role as either an oncogene or tumor suppressor depending on the cancer type highlights its complexity. Studies on RRAD using gene-knockout or conditional-knockout models (although not specifically detailed in the given references) could potentially further clarify its role in these biological processes and disease conditions, providing insights for targeted therapies.