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41 reviewsSUMMARYCuproptosis is a type of copper-induced cell death that mainly impacts cells relying on mitochondrial metabolism. Although p53 regulates glycolytic metabolism, its role in cuproptosis remains unclear. Here, wereport that the circular RNA, circFRMD4A, is crucial for p53-mediated metabolic reprogramming and cuproptosis. CircFRMD4A originates from the transcript of FRMD4A, which is transcriptionally activated by p53, andthe formation of circFRMD4A is facilitated by the RNA-binding protein EWSR1. CircFRMD4A functions as atumor suppressor and enhances the sensitivity of cancer cells to elesclomol-induced cuproptosis. Mechanistic analysis reveals that circFRMD4A interacts with and inactivates the pyruvate kinase PKM2, leadingto a decrease in lactate production and a redirection of glycolytic flux toward the tricarboxylic acid cycle.Finally, p53 agonists and elesclomol coordinately suppress the growth of cancer in a xenograft mouse model.Altogether, our study uncovers that p53 promotes glycolytic reprogramming and cuproptosis viacircFRMD4A and suggests a potential combination strategy against cancers with wild-type p53.INTRODUCTIONseveral mitochondrial proteins to enhance apoptosis.6,7 Recently,p53 was found to be a crucial modulator of ferroptosis.8,9 On theThe tumor suppressor p53 maintains genomic integrity and preone hand, p53 promotes ferroptosis by reducing the biosynthesisof glutathione (GSH)8,10 or regulating multiple metabolic pathwaysvents tumorigenesis by transcriptionally regulating the expressionof genes that are involved in the regulation of cell cycle and DNAthat are associated with peroxidation of polyunsaturated fattydamage repair.1 However, when cells have experienced irreversacids,11 glutamine catabolism,12–14 or vitamin K metabolism.15ible damage, p53 can trigger various forms of regulated cell deathOn the other hand, p53 increases GSH levels by elevating the(RCD) to eradicat