COMP-MUC1 interaction mediated by the Arg628-Asp543 salt bridge confers ferroptosis resistance to drive prostate cancer bone metastasis

Abstract Background Metastasis is the leading cause of mortality in prostate cancer (PCa), with bone being the most common site of dissemination. The survival of tumor cells in the circulation following detachment from the extracellular matrix (ECM) is an essential prerequisite for cancer metastasis, yet the underlying mechanisms remain incompletely understood. Methods To investigate the cellular adaptations that support survival under ECM-detached conditions, we established detachment-resistant (DR) models using PC-3 and LNCaP cells. COMP expression was examined in PCa clinical tissues and DR cells. Functional and mechanistic studies were then performed both in vitro and in vivo. Results COMP was highly expressed in PCa tissues and DR PCa cells. COMP upregulation promoted ferroptosis resistance by reducing intracellular Fe²⁺ accumulation and lipid peroxidation, thereby facilitating PCa progression and metastasis. Mechanistically, COMP directly bound to mucin 1 (MUC1) via a high-affinity Arg628-Asp543 salt bridge, which promoted MUC1 phosphorylation and enhanced its signaling activity. p-MUC1 subsequently inhibited the Hippo signaling pathway, promoting nuclear translocation of Yes-associated protein 1 (YAP1). YAP1 cooperated with TEAD transcription factors to drive transcription of nuclear protein 1 (NUPR1), which activated lipocalin-2 (LCN2), an iron-transporting protein that critically regulates intracellular iron homeostasis and redox balance, thereby conferring ferroptosis resistance. Importantly, suppressing COMP significantly inhibited PCa bone and lung metastasis in vivo. Conclusion This study reveals that COMP facilitates PCa bone metastasis by enhancing ferroptosis resistance through the MUC1/YAP1/NUPR1/LCN2 axis, suggesting that inhibition of COMP combined with ferroptosis activators may represent a promising therapeutic strategy to suppress PCa bone metastasis.