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

Sep 22, 2026

Uploaded by Margaret

Luminal breast cancer shows persistent recurrence risk and dysregulated lipid metabolism, yet the mechanism linking lipid remodeling to treatment response is not fully understood. Using multiomics data from a large luminal cohort (n = 773), the work identifies aberrant lipid metabolism as prognostically important and pinpoints DDHD2 as a copy-number alteration-driven cis-regulator. Mechanistically, AKT1-mediated phosphorylation induces DDHD2 phase separation to form condensates that raise lipase activity, reduce proferroptotic lipids, and lower ferroptosis susceptibility, while KLH45 inhibition enhances ferroptosis sensitivity and augments endocrine therapy efficacy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Significance

Luminal breast cancer and endocrine sensitivity

Recurrence and acquired resistance

Lipid metabolism and ferroptosis in breast cancer

Lipid reprogramming across subtypes

Phase separation as a regulatory mechanism

Condensates and spatiotemporal control

Phase separation of DDHD2 remodels lipid metabolism to dictate treatment sensitivity in luminal breast cancer Xiao-Hong Dinga, b, 1, Fenfang Chena, 1, Fan Yanga, 1, Gen-Hong Dia, b, Zhi-Ming Shaoa, b,2 , Yi Xiaoa, b,2 , and Yi-Zhou Jianga, b,c,2 Affiliations are included on p. 12. Edited by Leif W. Ellisen, Massachusetts General Hospital, Boston, MA; received February 10, 2025; accepted January 8, 2026 by Editorial Board Member Kornelia Polyak 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 cis-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. luminal breast cancer | DDHD2 | lipid metabolism | phase separation | ferroptosis Luminal breast cancer, characterized by the presence of estrogen receptor (ER), accounts for approximately two-thirds ofall breast cancer cases ( 1). Estrogen-driven ERα signaling cascades play a crucial role in the initiation and progression of luminal breast cancer, underpinning its high sensitivity to endocrine therapy (2–4) . Despite this sensitivity, the risk of both early and late recurrence exists due to the high level of intertumoral heterogeneity and the development of acquired resistance (5, 6) . Therefore, there is an urgent need to develop novel therapeutic strategies to improve the clinical management of patients with luminal breast cancer. Dysregulation of lipid metabolism has been increasingly recognized as a crucial regulator of tumor progression by providing energy sources and signaling molecules (7, 8) . Specifically, extensive studies have delineated distinct patterns of lipid metabolic reprogramming in breast cancer, particularly in basal-like and human epidermal growth factor receptor 2 (HER2)-enriched subtypes. For example, mitochondrial fatty acid β-oxidation is markedly enhanced in cancer stem cells, leading to metastasis and chemoresistance in basal-like breast cancer (9, 10). Meanwhile, trastuzumab-resistant HER2-positive tumors exhibit marked lipid metabolic reprogramming, which maybe orchestrated by genome-wide changes in histone modifications and chromatin architecture ( 11) . Moreover, excessive lipid peroxidation in cells triggers ferroptosis, a nonapoptotic form of regulated cell death that depends on iron-mediated oxidative damage and subsequent cell membrane rupture ( 12). Triple-negative breast cancer (TNBC) is exquisitely vulnerable to ferroptosis, while the luminal subtype is less sensitive to ferroptosis (13–15) . Notably, preclinical studies have shown that disrupting lipid metabolic pathways renders breast cancer cells more susceptible to chemotherapy, immunotherapy, and endocrine therapy ( 14, 16, 17) . Despite these advances, our understanding of the lipidomic landscape and the driving forces behind lipid metabolic shifts in luminal breast cancer remains lim

FAQs

What is the central finding about DDHD2 in luminal breast cancer?

DDHD2 acts as a cis-regulator that modulates lipid metabolism, and its condensates formed by phase separation reshape lipid reprogramming in luminal breast cancer.

How does DDHD2 phase separation affect ferroptosis susceptibility?

AKT1-mediated phosphorylation promotes DDHD2 phase separation, which enhances lipase activity, decreases proferroptotic lipid abundance, and reduces ferroptosis susceptibility.

Why does inhibiting DDHD2 matter therapeutically?

Inhibition of DDHD2 with KLH45 markedly increases ferroptosis sensitivity, restricts luminal breast cancer progression, and improves the efficacy of endocrine therapy when combined with ferroptosis inducers.

Sep 22, 2026

Uploaded by Margaret