Amentoflavone from Ginkgo biloba inhibits EMT-driven lung cancer metastasis by targeting TGFBR2: Integrative network pharmacology, machine learning, and experimental validation.
Liu K, Chen K, Zhao X, Zhang Y, Cai Y
Summary
7.1/10Researchers discovered that amentoflavone, a natural compound from Ginkgo biloba, can prevent lung cancer from spreading by blocking a key protein involved in cancer cell migration. Laboratory and animal studies show the plant-derived compound successfully stopped cancer metastasis without the severe side effects typical of conventional treatments.
Key Findings
Machine learning model achieved 95.1% accuracy (AUC 0.951) on internal testing and 81.4% accuracy (AUC 0.814) on external validation, demonstrating robust predictive power for target identification
Amentoflavone reduced lung cancer cell migration by downregulating TGFBR2 protein and inhibiting Smad2/3 phosphorylation, effectively reversing epithelial-mesenchymal transition (EMT)
In vivo mouse studies confirmed AMF suppressed pulmonary metastasis by dampening the TGF-β/Smad signaling pathway, with no significant toxicity observed
Original Abstract
In non-small cell lung cancer (NSCLC), fatal outcomes predominantly result from metastatic dissemination, highlighting an urgent need for metastasis-directed therapies. Amentoflavone (AMF), a natural biflavonoid found in Ginkgo biloba and other medicinal plants, exhibits known antitumor activity. However, its role in NSCLC metastasis and the underlying mechanisms remain poorly understood. This study aimed to investigate the anti-metastatic effects of AMF from Ginkgo biloba in NSCLC and to elucidate the underlying molecular mechanisms. A network pharmacology approach combined with machine learning was used to predict AMF targets and derive a core diagnostic gene signature. Molecular docking and 100-ns molecular dynamics simulations were performed to characterize AMF-target binding and stability. In vitro, NSCLC cell migration was assessed using wound-healing (scratch) assays and Transwell migration chambers, with mechanistic insights obtained by Western blot analysis of EMT-related proteins. In vivo efficacy was evaluated in a murine pulmonary metastasis model established via tail-vein tumor cell injection. The machine learning model achieved an AUC of 0.951 in the internal testing set and 0.814 in the external validation set (GSE31210), indicating high robustness. Convergent computational analyses identified TGFBR2 as a key candidate target of AMF. Docking and 100-ns MD simulations predicted a strong and dynamically stable binding mode of AMF to TGFBR2. In vitro, AMF significantly reduced NSCLC cell migration, accompanied by downregulation of TGFBR2 and inhibition of Smad2/3 phosphorylation, which collectively reversed epithelial-mesenchymal transition (EMT). Consistently, AMF suppressed NSCLC metastasis in vivo by inhibiting the TGF-β/Smad signaling pathway. Our data indicate that AMF functions as an anti-metastatic agent in NSCLC at least in part by downregulating TGFBR2, thereby dampening TGF-β/Smad signaling and preventing EMT. These findings highlight AMF as a promising natural candidate for developing anti-metastatic therapies that appear well tolerated under the conditions tested.
Species Mentioned
Ginkgo biloba, commonly known as ginkgo, also known as the maidenhair tree, and often misspelled "gingko" is a species of gymnosperm tree native to East Asia. It is the last living species in the order Ginkgoales, which first appeared over 290 million years ago. Fossils similar to the living spec...
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