Targeted nanoemulsion Blocks MTFR2-HIF-1α-EZH2/FoxM1 axis to suppress tongue squamous cell carcinoma invasion and metastasis

OBJECTIVE: Tongue squamous cell carcinoma (TSCC) is characterized by high invasiveness and early lymph node metastasis, leading to a poor prognosis.Current surgical and chemoradiotherapy regimens often cause functional impairment, drug resistance, and other drawbacks. Thus, developing highly effective, lowtoxicity treatments is a key research priority. Traditional Chinese medicine (TCM) offers unique advantages via multitarget synergistic effects, enabling innovative therapeutic approaches. METHOD: In this study, we developed Astragaloside IV-Brucea javanica oil nanoemulsion (AS/BJO-NEs) and characterized its stability, polydispersity, and pharmacokinetic profile. The effects of AS/BJO-NEs on TSCC cells were evaluated through a series of functional assays, including CCK-8 (viability), colony formation (proliferation), and scratch wound healing (migration). Both in vitro and in vivo experiments were performed to investigate whether its mechanism involves regulation of the MTFR2-HIF-1α-EZH2/FoxM1 signaling axis. RESULTS: The optimized AS/BJONEs exhibited uniform spherical morphology at the nanoscale and demonstrated favorable stability. In both in vitro and in vivo models, AS/BJONEs significantly suppressed the malignant phenotype of TSCC cells. Mechanistic investigation further revealed that the anti-tumor effects of AS/BJONEs are mediated, at least in part, through targeting the MTFR2-HIF-1α-EZH2/FoxM1 signaling axis, as confirmed by establishing stable MTFR2/HIF-1α knockdown and overexpression cell models. CONCLUSION: This study demonstrates that AS/BJONEs inhibit TSCC progression by targeting the MTFR2-HIF-1α-EZH2/FoxM1 signaling axis. Our findings provide experimental evidence supporting the development of multi-target therapeutic strategies derived from traditional Chinese medicine for the treatment of TSCC.