Colorectal cancer (CRC) is a highly lethal gastrointestinal malignancy, and its progression is closely related to abnormal protein O-GlcNAcylation modifications, especially during extracellular matrix (ECM) remodeling. Kaempferol is a natural flavonoid with medicinal value that can inhibit CRC progression through various pathways. However, it is unclear whether its mechanism of action involves O-GlcNAc-driven metabolic reprogramming. This study confirmed that kaempferol can significantly inhibit CRC growth both in vitro and in vivo and effectively reduce the overall protein O-GlcNAcylation levels. Mechanistic studies indicate that kaempferol reduces the levels of substrate uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and downregulates the expression of O-GlcNAc transferase (OGT), thereby decreasing the O-GlcNAcylation levels of proteins. This leads to a reduction in the O-GlcNAc modification of downstream heat shock protein 47 (Hsp47), which in turn affects the expression and intracellular localization of Hsp47, ultimately inhibiting the maturation and secretion of type I collagen, thereby blocking CRC progression. This study reveals a new mechanism by which kaempferol inhibits CRC by targeting the O-GlcNAcylation pathway. The study results suggest that O-GlcNAc-modified Hsp47 could serve as a potential therapeutic target for CRC and propose a treatment strategy guided by flavonoid biomarkers based on the inhibition of the OGT-collagen axis.
Keywords: Colorectal Cancer; Hsp47; Kaempferol; O-GlcNAc; OGT.
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