Phase separation of DDHD2 remodels lipid metabolism to dictate treatment sensitivity in luminal breast cancer

Luminal breast cancer is characterized by a persistent risk of recurrence and dysregulated lipid metabolism. However, the role of phase separation, a novel mechanism for the spatial compartmentalization of proteins, in lipid remodeling within the context of breast cancer remains largely unexplored. Utilizing the multiomics data from our large breast cancer cohort (n = 773), we revealed that aberrant lipid metabolism negatively impacts the prognosis of patients with luminal breast cancer. Furthermore, we deciphered that the copy number alteration-driven <i>cis</i>-regulation of DDHD domain containing 2 (DDHD2) is correlated with lipid remodeling in luminal breast cancer. Mechanistically, DDHD2 forms biomolecular condensates through phase separation upon AKT1-mediated phosphorylation, which enhances its lipase activity, reduces the abundance of proferroptotic lipids, and consequently decreases ferroptosis susceptibility. Therapeutically, the DDHD2 inhibitor KLH45 remarkably enhances ferroptosis sensitivity to restrict luminal breast cancer progression, and its combination with ferroptosis inducers further improves the efficacy of endocrine therapy. Collectively, our findings reveal a key role of DDHD2 condensates in lipid reprogramming and propose an innovative therapeutic strategy for luminal breast cancer.