PRODH2-Mediated Regulation of Hydroxyproline Metabolism in the Bone Microenvironment Promotes Breast Cancer Bone Metastasis via Ferroptosis Suppression and Osteoclast Differentiation

The role of amino acid metabolism in the bone metastatic microenvironment of breast cancer (BC) remains inadequately characterized. In this study, we focused on hydroxyproline (Hyp) metabolism, a key amino acid resulting from bone collagen degradation, which serves as a critical biomarker for bone metastases. Our findings reveal that proline dehydrogenase 2 (PRODH2), the primary enzyme involved in Hyp metabolism, is significantly upregulated in clinical samples from BC bone metastases. Notably, PRODH2-mediated Hyp metabolism plays a crucial role in driving osteoclast differentiation, enhancing collagen degradation, and promoting tumor bone metastasis in vivo. Furthermore, PRODH2 facilitates tumor cell viability and osteoclast differentiation by upregulating the ferroptosis inhibitor SLC7A11 and the bone metastasis-related factor IL-8, respectively. Both the SLC7A11 and IL-8 promoters are subject to the regulatory control of the transcription factor YY1. Intriguingly, the Hyp metabolism catalyzed by PRODH2 generates acetyl-CoA, which enhances YY1 acetylation, thereby transcriptionally activating both SLC7A11 and IL-8. These results revealed a vicious cycle in the bone metastatic microenvironment: collagen degradation from osteolysis produced Hyp, which reinforced osteoclast differentiation and metastasis. Importantly, treatment with a PRODH2 inhibitor effectively disrupted this bone metastatic cascade. These findings underscored the significance of the PRODH2-SLC7A11/IL-8 axis in breast cancer bone metastasis and suggested potential therapeutic strategies.