Hedyotis diffusa Willd. inhibits pulmonary metastasis of cancer through suppression of Src/FAK signaling.

[BACKGROUND] Hedyotis diffusa Willd. (HDW), a traditional Chinese medicine, has been widely used to combat cancer in China. While HDW demonstrates anti-metastatic potential, its precise mechanisms of action remain largely unknown.

[PURPOSE] To investigate the effects of HDW on regulating cancer lung metastasis and to elucidate its underlying mechanism.

[METHODS] Cell proliferation was assessed using the CCK-8 assay, while cell adhesion assays were performed to evaluate tumor cell binding to the extracellular matrix, platelets, and pulmonary microvascular endothelial cells (HPMECs). Flow cytometry and immunofluorescence staining were used to detect tumor cell interactions with platelets and pulmonary ECs. A circulating tumor cell (CTC) line derived from human lung cancer was utilized to evaluate the impact of HDW on CTCs. A hematogenous lung metastasis mouse model was established to assess in vivo metastasis.

[RESULTS] HDW exhibited stronger inhibitory effects on cancer cell proliferation when administered prior to cell adhesion compared to post-cell adhesion, which differs from conventional chemotherapy agents. Furthermore, HDW markedly inhibited tumor cell adhesion to extracellular matrix, platelets, and HPMECs, processes critical for inhibiting hematogenous metastasis. Compound identification and network pharmacology analysis revealed FAK and Src as key targets of HDW. Inhibiting Src/FAK signaling pathway significantly blunted the effects of HDW on tumor cell adhesion. In a hematogenous metastasis mouse model, HDW significantly decreased tumor cell adhesion to platelets and ECs and reduced the incidence of lung metastasis.

[CONCLUSION] HDW prevents cancer lung metastasis by suppressing tumor cell adhesion through inhibition of Src/FAK pathway. This study elucidates novel mechanisms underlying HDW's inhibitory effects on pulmonary cancer dissemination, revealing its therapeutic potential against metastatic progression.