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20(S)-Ginsenoside Rg3 suppresses lung cancer-associated fibroblast activation associated with IL-17RD-FGF-MAP2K4-JNK
Xinyu Zhang1,2, Lei Xia1, Feng Cheng2,3
1Fuzong Teaching Hospital of Fujian University of Traditional Chinese Medicine (900th Hospital), Fuzhou, China.
Abstract:
Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that contribute to tumor progression and therapeutic resistance in non-small cell lung cancer (NSCLC). However, effective strategies targeting CAF regulation remain limited. Here, we investigated the effects of the plant-derived compound 20(S)-Ginsenoside Rg3 on CAFs using an integrated network pharmacology and experimental validation approach. Network pharmacology analysis identified 107 overlapping targets between Rg3 and NSCLC. PPI network analysis highlighted EGFR, JUN, TP53, and STAT3 as key hub genes. KEGG enrichment analysis indicated that these targets were significantly enriched in the IL-17 and MAPK signaling pathways. These genes and pathways have been associated with fibroblast activation and tumor stromal remodeling, suggesting a potential role of Rg3 in regulating CAF-related processes within the tumor microenvironment. Functional experiments demonstrated that Rg3 inhibited CAF proliferation, colony formation and migration, while inducing apoptosis and mitochondrial dysfunction. Mechanistically, Rg3 upregulated IL-17RD and suppressed FGFR1-MAP2K4-JNK-c-Jun signaling. Furthermore, co-culture experiments revealed that Rg3-treated CAFs exhibited reduced pro-tumorigenic effects on NSCLC cells, indicating impaired tumor-stroma communication. Collectively, these findings demonstrate that 20(S)-Ginsenoside Rg3 suppresses CAF activation and function associated with the IL-17RD-FGF-MAP2K4-JNK-c-Jun signaling pathway, highlighting its potential as a tumor microenvironment-targeted therapeutic agent in NSCLC.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s10616-026-00957-1.
Insights
The plant compound 20(S)-Ginsenoside Rg3 effectively suppresses cancer-associated fibroblasts (CAFs) in non-small cell lung cancer (NSCLC). This natural agent targets key signaling pathways, reducing tumor progression and offering potential for novel microenvironment-based therapies.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Cancer-associated fibroblasts (CAFs) are crucial in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC), promoting tumor growth and treatment resistance.
- Current strategies to target CAF regulation in NSCLC are limited, necessitating the exploration of novel therapeutic agents.
Purpose of the Study:
- To investigate the effects of 20(S)-Ginsenoside Rg3, a plant-derived compound, on CAFs within the NSCLC TME.
- To elucidate the molecular mechanisms underlying Rg3's action on CAFs and their interaction with NSCLC cells.
Main Methods:
- Integrated network pharmacology and experimental validation approaches were employed.
- Network analysis identified key targets and signaling pathways (e.g., IL-17, MAPK) involved in Rg3's interaction with NSCLC.
- In vitro functional assays assessed Rg3's impact on CAF proliferation, migration, apoptosis, and mitochondrial function.
Main Results:
- Rg3 demonstrated significant inhibition of CAF proliferation, colony formation, and migration, while inducing apoptosis and mitochondrial dysfunction.
- Mechanistically, Rg3 modulated the IL-17RD-FGF-MAP2K4-JNK-c-Jun signaling pathway.
- Rg3-treated CAFs exhibited reduced pro-tumorigenic effects on NSCLC cells, indicating disrupted tumor-stroma communication.
Conclusions:
- 20(S)-Ginsenoside Rg3 effectively suppresses CAF activation and function in NSCLC.
- Rg3 acts via the IL-17RD-FGF-MAP2K4-JNK-c-Jun signaling pathway, highlighting its potential as a TME-targeted therapeutic agent for NSCLC.
