Disruption of PI3K-OxPhos Coupling by Trehalose Drives a BCAA-to-Lipid Metabolic Switch in Hormone-Receptor–Positive Breast Cancer

Cancer cells sustain proliferation through dynamic coordination between mitochondrial oxidative phosphorylation (OxPhos) and anabolic carbon metabolism. How this metabolic coupling can be selectively destabilized in subtype-specific contexts remains poorly defined. Here we identify trehalose, a disaccharide previously linked to autophagy modulation, as a regulator of mitochondrial–anabolic integration in breast cancer. Using high-resolution respirometry, untargeted metabolomics, and signalling analyses across estrogen/progesterone receptor–positive (ER⁺) and triple-negative models, we show that trehalose preferentially impairs mitochondrial bioenergetics in OxPhos-dependent ER⁺ cells. Trehalose reduced electron transport system capacity, NADH-linked respiration, mitochondrial membrane potential, and coupling efficiency, while suppressing mitochondrial biogenesis markers. These bioenergetic effects coincided with attenuation of PI3K/Akt signalling and induction of p21-associated growth arrest. Metabolomic profiling revealed a coordinated redistribution of carbon flux characterized by depletion of branched-chain amino acids (BCAAs) and glycolytic intermediates alongside accumulation of long-chain fatty acids and cholesterol. Correlation network analysis uncovered a strong inverse relationship between BCAA-linked metabolism and lipid abundance, indicating a regulated metabolic trade-off rather than nonspecific stress. Functionally, trehalose enhanced the efficacy of mitochondrial-interfering agents such as tamoxifen and colchicine, while exerting minimal effects in metabolically flexible triple-negative cells. Together, these findings define trehalose as a metabolic modulator that constrains mitochondrial plasticity and enforces a lipid-buffered, growth-restrictive state in ER⁺ breast cancer, revealing a therapeutic vulnerability linked to mitochondrial dependency.