## 4 Discussion
This aligns with the docking results of the current study, reinforcing the therapeutic relevance of these ginseng in AML and other cancers, particularly in the context of inflammation and tumor progression. Furthermore, given the structural similarities between dexamethasone, a well-established anti-inflammatory and anticancer agent, and ginsengides, these findings collectively highlight the need for further experimental validation to explore the therapeutic potential of predicted ginsengides in AML and other malignancies. The minimal CYP interaction and low toxicity, highlight that ginsengides could be low-toxicity alternatives for cancers with elevated ADGRG3 expression [80; 81; 82; 83; 84]. The MDS and free binding energy calculations (MMPBSA) further supported these findings, demonstrating that the ginseng-ADGRG3 complexes are stable, with maintained flexibility and the formation of stable hydrogen bonds throughout the simulation. This stability suggests that these ginsengides could possibly modulate ADGRG3. Notably, natural compounds such as curcumin have also been shown to modulate GPR97, further emphasizing the potential of natural products in targeting this receptor [85]. Future studies should incorporate experimental validation (e.g., SPR, ITC, or functional assays) to confirm the pharmacological relevance of ginsengides in targeting ADGRG3. The pathway and protein-protein interaction analyses further connected ADGRG3 to critical GPCR and immune pathways, such as neutrophil degranulation and Ca\({}^{2+}\) signaling, both essential in cancer progression and immune modulation. ADGRG3's associations with immune cell infiltration in cancers such as HNSC, where it correlated with CD8+ T cells and macrophages, suggest it plays a role in the tumor microenvironment and immune response. Ginsenosides, through their interactions with ADGRG3, may influence these pathways, potentially enhancing immune responses or altering the tumor microenvironment to improve outcomes. Notably, ginsenoside Rg3 has been shown to suppress neutrophil migration, as observed in COPD models, highlighting its potential to modulate neutrophil degranulation pathways. In cancer, Rg3 has demonstrated anti-leukemic effects by inhibiting HIF-1\(\alpha\) and VEGF expression via the PI3K/Akt and ERK1/2 pathways and suppressing vasculogenic mimicry through the regulation of VE-cadherin/EphA2/MMP9/MMP2 expression. Similarly, ginsenoside compound K (CK) exhibits anticancer properties in acute myeloid leukemia and liver cancer, inducing ferrotptosis via the FOXO pathway and exerting in vivo anti-leukemic effects. These findings provide understandings into the ability of ginsenosides to modulate key signaling pathways involved in tumor progression and immune regulation, further supporting their targeting potential for ADGRG3 [86; 87; 88; 89; 90; 91; 92]. The gene expression analysis of 506 AML samples revealed heterogeneous ADGRG3 expression, with high levels in 70-80% of samples, reflecting the diverse clinical and biological profiles of AML patients. Genes such as GNB1, GNG2, CSF3R, and ATP6V0B showed consistently high expression, highlighting their roles in GPCR signaling, immune modulation, and neutrophil activity. Previous studies have linked GNG2 to GPCR signaling and inflammation, as seen in _Panax ginseng_ research, and CSF3R to neutrophil activity, with ginsenoside Rg3 reducing cancer drug toxicity. CXCL8, another inflammatory mediator, is highly expressed in AML, with studies showing that modified ginseng extract effectively blocks CXCL8-mediated Akt/NF-kB signaling in cancer models. Hierarchical clustering revealed co-expression of GPCR-related genes (ADGRG3, GNB1, and GNG2) and inflammatory mediators (IL8, CSF3R, and CCL2), underscoring their interplay in AML. These findings, combined with the findings of previous studies on ginsenosides, highlight their therapeutic relevance in modulating AML-specific pathways [93; 94; 95]. In summary, this study predicted that ginsenosides could be natural modulators of ADGRG3.