Guizhi-Fuling Wan suppresses carcinoma-associated mesenchymal stem cells-induced ovarian cancer progression via STAT3 inhibition

BACKGROUND: Ovarian cancer (OC) is the most lethal gynecological malignancy. While carcinoma-associated mesenchymal stem cells (CA-MSCs) in tumor microenvironment are known to facilitate OC progression, the underlying mechanisms remain incompletely understood. The classical herbal formula Guizhi-Fuling Wan (GZFL) has demonstrated significant clinical efficacy in OC maintenance therapy, however, its therapeutic mechanisms require further exploration for precision clinical applications. METHODS: Immunohistochemical analysis of 45 ovarian tumor specimens revealed the clinical significance of p-STAT3 expression and CA-MSCs filtration patterns. Mechanistic studies employed STAT3 knockout (KO) cell lines. To evaluate the tumor-promoting effects of CA-MSCs and the therapeutic potential of GZFL, cancer cells were co-cultured with CA-MSCs and assessed using anti-proliferation, 3D spheroid formation, transwell invasion assays, and in vivo xenograft models. EMT-related protein expression was assessed in co-culture systems to further validate the biological activity of GZFL. RESULTS: Clinically, STAT3 activation strongly correlated with CA-MSCs infiltration as well as with OC progression. We found that CA-MSCs promote OC proliferation and metastasis through a mechanism mediated by STAT3, as STAT3 KO cells showed markedly reduced responsiveness. GZFL effectively blocked CA-MSCs-induced proliferation and metastasis both in vitro and in mice. Further molecular analyses revealed that GZFL disrupted the tumor-stromal crosstalk by suppressing the STAT3-EMT signaling axis. CONCLUSION: Our study identifies STAT3 as a key regulator of CA-MSCs-induced OC progression and highlights the therapeutic potential of GZFL, which targets the STAT3-mediated tumor-stromal crosstalk. Our findings provide crucial mechanistic basis for advancing the clinical application of GZFL for the treatment of metastatic OC.