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bioRxiv · 10.64898/2026.04.14.718262

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

Singh, T.·Kaur, P.·Munshi, A.·Singh, S.
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Abstract

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.

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Singh, T., Kaur, P., Munshi, A., Singh, S.. 2026-04-17. Disruption of PI3K/OxPhos Coupling by Trehalose Drives a BCAA to Lipid Metabolic Switch in Hormone Receptor Positive Breast Cancer. https://doi.org/10.64898/2026.04.14.718262

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