## 1 Introduction  
The human genome provides a wealth of potential therapeutic targets, making drug-gable targets essential in drug discovery. Advances in genomics have expanded the concept of the \"druggable genome\" to include molecular entities that can be manipulated to enhance health, revolutionizing the drug discovery process from \"forward pharmacology\" to \"reverse pharmacology\" [1, 2, 3, 4, 5, 6]. Novel druggable targets identified through genome sequencing have significantly accelerated drug development [5, 7]. Tools such as AlphaFold, an AI-based protein structure prediction method, further enhance this process by enabling large-scale drug screening, improving target-ligand interaction studies, and facilitatingthe identification of molecules from the druggable genome/proteome [3; 8]. These system-based technologies, including cellular gene expression profiling and in silico modeling, have led to more efficient pipelines to predict novel therapeutics. G-protein-coupled receptors (GPCRs), the largest family of membrane receptors, have been extensively studied in cancer- and immune-related diseases due to their crucial roles in cellular signaling and disease pathways [3; 7; 9; 10; 11; 12; 13; 14]. Among them, the adhesion G-protein-coupled receptor G3 (ADGRG3 or GPR97) has gained interest due to its potential involvement in cancer progression and immune modulation [15; 16; 17]. The classical adhesion structure of GRP97 has seven transmembrane helices, an N-terminal fragment, and a C-terminal fragment that results from autoproteolytic cleavage at a GPCR-proteolytic site contained in a juxtamembranous GPCR autoproteolysis-inducing domain [16]. ADGRG3/GPR97 has been identified in leukocytes, including eosinophils, neutrophils, and mast cells [18], and it plays a role in macrophage-related diseases and obesity-induced metabolic disorder [19]. Additionally, it has been documented that ADGRG3/GPR97 is expressed in spinal cord endothelial cells in naive mice and is elevated in spinal cord endothelial cells and spinal cord-infiltrating CD4+ T cells of MOG-immunized mice during the onset of disease [20]. ADGRG3/GPR97 is essential for controlling the destiny of B cells, particularly for controlling the activities of nuclear factor (NF)-kB and constitutive cAMP response element-binding protein [21]. These results suggest that ADGRG3/GPR97 may play a role in the emergence of immune diseases and cancers. However, unlike well-studied GPCRs such as ADGRG1, ADGRG3 has not been thoroughly researched, despite evidence of its differential expression in cancers such as leukemia and its association with immune cell pathways [17; 22]. Notably, a recent study demonstrated that another adhesion GPCR, ADGRE2, plays a critical role in Acute Myeloid Leukemia (AML) by promoting leukemic stem cell survival and tumor progression via the MEK/AP1/DUSP1 axis. This role was experimentally validated through both in vitro and in vivo studies, where ADGRE2 knockdown in AML cell lines and patient-derived cells significantly impaired cell proliferation, induced apoptosis, and reduced leukemic stem cell (LSC) frequency. Moreover, in xenograft mouse models, ADGRE2 silencing delayed leukemia progression and prolonged survival, providing strong evidence for the functional relevance of adhesion GPCRs in AML pathogenesis [23]. Given the structural and functional similarities among adhesion GPCRs, this finding underscores the potential role of ADGRG3 in leukemia, suggesting that it may similarly contribute to disease progression and serve as a promising target for further investigation. Natural products have historically been a cornerstone of drug discovery, especially in oncology, due to their structural diversity and biological activities [24; 25]. Triterpenoids, a prominent class of plant-derived compounds, demonstrate significant potential as anti-cancer agents [26].