A microprotein encoded by LINC00263 promotes breast cancer osteolytic bone metastasis by inducing osteoclastogenesis and inhibiting osteoclast ferroptosis.

Currently, there are no effective prevention or therapeutic methods for breast cancer bone metastasis (BC-BM), which leading to severe skeletal complications and increased mortality. Understanding the mechanisms underlying BC-BM could provide potential strategies for its prevention and treatment. In this study, we identified a new microprotein encoded by lncRNA LINC00263, which we named LINC00263-encoded protein (LINC00263-P), was significantly upregulated in bone metastatic breast cancer tissues and correlated with BC-BM. Overexpression of LINC00263 significantly promoted BC-BM, while treatment with the neutralizing anti-LINC00263-P antibody effectively inhibited BC-BM. Mechanically, the LINC00263-P binds to integrin αvβ3 for activating Src/Syk/Vav-3 axis and yes-associated protein 1 (YAP1) pathway, which enhanced osteoclastogenesis and diminishes ferroptosis in osteoclasts, thereby creating an osteolytic bone metastasis niche that fosters BC-BM. Importantly, treatment with angoroside C, an active component from the traditional Chinese medicine Scrophulariae Radix extract, effectively blocked the binding of LINC00263-P to αvβ3, thereby inhibiting abnormal osteoclastogenesis and preventing BC-BM. These findings highlight the crucial role of microprotein LINC00263-P in disrupting bone homeostasis and propose a potential molecular mechanism of BC-BM.