Compelling evidence suggests that tumor initiating cells (TIC) are the roots of current shortcomings in advanced and metastatic cancer treatment. TIC represents a minor subpopulation of tumor cells endowed with self-renewal and multi-lineage differentiation capacity, which can disseminate and seed metastasis in distant organ. Our work identified Streptomycin (SM), a potent bactericidal antibiotic, as a new molecule capable of targeting non-adherent TIC from colon and breast cancer cell lines by inducing mitochondrial-dependent ferroptosis. SM-induced ferroptosis associates with profound alterations in mitochondrial morphology, such as swelling and cristae enlargement, coupled with hyperpolarization of mitochondrial membrane potential and production of mitochondrial ROS. The peculiar SM structure, and more particularly its aldehyde group, is essential for this mechanism. As such, the mere reduction of SM into dihydrostreptomycin abolishes its effect on TICs. This study reveals a new mechanism of action of SM that could help comprehend the molecular basis of TIC adaptation to inhospitable environments and pave the way for new treatment of advanced cancers.

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