De novo lipogenesis protects dormant breast cancer cells from ferroptosis and promotes metastasis Puente Cobacho, Beatriz Esteo, Cintia Altea-Manzano, Patricia García Pérez, José Luis Quiles, José L. Sanchez-Rovira, Pedro Martín-Salvago, María D. Molina Jiménez, Lucía Luque, Rafael J. Fendt, Sarah Maria Vera Ramírez, Laura Tumor cell dormancy Breast cancer metastasis Dormant disseminated tumor cells (DTCs) remain viable for years to decades before establishing a clinically overt metastatic lesion. DTCs are known to be highly resilient and able to overcome the multiple biological hurdles imposed along the metastatic cascade. However, the specific metabolic adaptations of dormant DTCs remain to be elucidated. Here, we reveal that dormant DTCs upregulate de novo lipogenesis and favor the activation and incorporation of monounsaturated fatty acids (MUFAs) to their cellular membranes through the activation of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3). Pharmacologic inhibition of de novo lipogenesis or genetic knockdown of ACSL3 results in lipid peroxidation and non-apoptotic cell death through ferroptosis. Clinically, ACSL3 was found to be overexpressed in quiescent DTCs in the lymph nodes of breast cancer patients and to significantly correlate with shorter disease-free and overall survival. Our work provides new insights into the molecular mechanisms enabling the survival of dormant DTCs and supports the use of de novo lipogenesis inhibitors to prevent breast cancer metastasis. 2025-02-27T10:47:35Z 2025-02-27T10:47:35Z 2025-01-09 journal article Beatriz Puente-Cobacho, Cintia Esteo, Patricia Altea-Manzano, Jose Luis Garcia-Perez, José L. Quiles, Pedro Sanchez-Rovira, María D. Martín-Salvago, Lucía Molina-Jiménez, Rafael J. Luque, Sarah-Maria Fendt, Laura Vera-Ramirez, De novo lipogenesis protects dormant breast cancer cells from ferroptosis and promotes metastasis, Redox Biology, Volume 80, 2025, 103480, ISSN 2213-2317, https://doi.org/10.1016/j.redox.2024.103480 https://hdl.handle.net/10481/102770 10.1016/j.redox.2024.103480 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier