PRODH2-Mediated Metabolism in the Bone Microenvironment Promotes Breast Cancer Metastasis

Abstract Breast cancer frequently metastasizes to the bone, but treatment options for bone metastatic breast cancer are limited. Amino acid metabolism is reprogrammed in the bone metastatic microenvironment, suggesting that it could represent a therapeutic vulnerability. In this study, we focused on the metabolism of hydroxyproline (Hyp), a key amino acid resulting from bone collagen degradation, which serves as a critical biomarker for bone metastases. Proline dehydrogenase 2 (PRODH2), the primary enzyme involved in Hyp metabolism, was significantly upregulated in clinical samples from breast cancer bone metastases. Notably, PRODH2-mediated Hyp metabolism drove osteoclast differentiation, enhancing collagen degradation and promoting breast cancer bone metastasis in vivo. Furthermore, PRODH2 facilitated tumor cell viability and osteoclast differentiation by upregulating the ferroptosis inhibitor SLC7A11 and the bone metastasis–related factor CXCL8 (IL8), respectively. Intriguingly, Hyp metabolism catalyzed by PRODH2 generated acetyl-CoA, which enhanced YY1 acetylation and thereby transcriptionally activated both SLC7A11 and IL8. Importantly, treatment with a PRODH2 inhibitor effectively disrupted the bone metastatic cascade. Together, these results reveal that collagen degradation from osteolysis produces Hyp that reinforces osteoclast differentiation and metastasis, creating a vicious cycle. Identification of the role of the PRODH2–SLC7A11–IL8 axis in promoting breast cancer bone metastasis suggests potential therapeutic strategies to improve patient outcomes. Significance: In the bone microenvironment, osteolysis increases PRODH2-mediated hydroxyproline metabolism that drives osteoclast differentiation and suppresses breast cancer cell ferroptosis, which can be reversed by targeting PRODH2 to suppress metastatic progression.