Dietary D-mannose from fruits as a natural metabolic modulator against breast cancer: Targeting the Warburg effect for precision nutrition intervention

Cancer cells’ preferential reliance on glucose metabolism creates therapeutic opportunities for food-derived metabolic modulators. D-mannose, a glucose analog naturally abundant in cranberries, apples, and other common fruits, represents a promising nutritional intervention that can selectively target cancer metabolism while preserving normal cellular function. This study investigated the anticancer efficacy of fruit-derived D-mannose against breast cancer and elucidated its metabolic regulatory mechanisms using integrative approaches. Four molecularly distinct breast cancer cell lines were treated with D-mannose to evaluate cytotoxicity and apoptosis induction. Comprehensive metabolomics, ¹³C-glucose flux analysis, and xenograft studies assessed central carbon metabolism reprogramming and therapeutic efficacy. D-mannose demonstrated subtype-specific anticancer activity while sparing normal breast epithelial cells. Metabolomic analysis revealed sophisticated multi-pathway disruption, including upstream glycolytic intermediate accumulation with dramatic lactate reduction, tricarboxylic acid cycle reprogramming, and pentose phosphate pathway bottlenecks that deprive cancer cells of biosynthetic precursors. ¹³C-flux analysis confirmed impaired glucose utilization across metabolic networks, with cancer cells unable to compensate due to metabolic inflexibility. <em>In vivo</em> validation demonstrated significant tumor growth inhibition with excellent safety profiles. Plasma analysis confirmed systemic metabolic normalization and significant inhibition of key glycolytic enzymes. These findings establish D-mannose as a sophisticated food-derived metabolic modulator that exploits cancer's glucose dependency through competitive interference, demonstrating how naturally occurring fruit sugars can serve as precision nutrition tools for breast cancer intervention. This research advances evidence-based functional food development and validates the “food as medicine” paradigm for safer, accessible cancer prevention and complementary therapy strategies.