Targeting Netrin-1 Mediates the Suppression of Osteolytic Bone Metastasis in Breast Cancer by Ugonin L.

Over 70% of patients experience bone metastases, a serious and crippling side effect of breast cancer that increases morbidity. There is an urgent need for innovative therapies because current therapeutic options, including systemic and local treatments, are limited by significant side effects and poor survival improvements. Helminthostachys zeylanica is the source of Ugonin L, a naturally occurring substance with established anti-inflammatory properties. However, its role in breast cancer-associated osteolytic bone metastasis remains elusive. Here, we demonstrate that Ugonin L suppresses epithelial-mesenchymal transition (EMT), migration, and invasion of breast cancer cells. We identify Netrin-1 (NTN-1) as a critical mediator of Ugonin L-induced inhibition of EMT and cell motility. Clinical data analyses revealed that elevated NTN-1 expression is significantly linked with disease progression, poor overall survival, and bone metastasis in breast cancer patients. Mechanistically, Ugonin L inhibits NTN-1-dependent EMT and motility by suppressing the canonical Wnt/β-catenin signaling pathway. Furthermore, Ugonin L attenuates breast cancer-promoted osteoclast differentiation by downregulating NTN-1 expression. Importantly, Ugonin L markedly suppresses breast cancer-induced osteolytic bone lesions in vivo. Collectively, these results position Ugonin L as a promising therapeutic candidate for the prevention and remedy of osteolytic bone metastasis in breast cancer.