Kaempferol exerts anti-colorectal cancer effects through its multi-target mediated glucose metabolism remodeling

Kaempferol is a natural flavonoid that exhibits antitumor activity; however, its mechanism of action in colorectal cancer (CRC), particularly its multi-target effects in regulating the glucose metabolism network, still lacks a systematic elaboration. In this study, we integrated metabolomics, molecular docking and cellular thermal shift assay to systematically reveal that kaempferol exerts its anti-CRC effects by disrupting glycolysis and the pentose phosphate pathway while enhancing oxidative phosphorylation (OXPHOS). At the mechanistic level, on the one hand, kaempferol targets and enhances OXPHOS mediated by mitochondrial transcription factor A (TFAM). This induces a sharp increase in reactive oxygen species levels and the collapse of the mitochondrial membrane potential, thereby activating apoptosis. On the other hand, it inhibits transketolase (TKT) in the PPP and aldolase A (ALDOA) in glycolysis, which blocks the supply of raw materials required for nucleic acid synthesis, thus inhibiting DNA synthesis and tumor cell proliferation. In conclusion, this study confirms that kaempferol disrupts the metabolic homeostasis of cancer cells across multiple dimensions, including energy metabolism, biosynthesis, and oxidative stress, indicating its potential for development as a novel anti-colorectal cancer drug targeting tumor metabolism.