Triptolide from Suppresses Glycolysis and Induces Cuproptosis via the HK2/DLAT Signaling Pathway in Colorectal Cancer.

Colorectal cancer (CRC) exhibits high mortality due to tumor cell dissemination. Surgical resection combined with chemotherapy is the primary treatment, but chemoresistance often limits its efficacy against metastasis. Cuproptosis, a novel cell death mechanism regulating mitochondrial and lipid metabolism, may suppress metastasis by inhibiting cellular metabolism. Triptolide (TP), a potential antitumor agent derived from , can reverse chemoresistance. This study investigated the link between TP's anti-CRC effects and cuproptosis. Cell Counting Kit-8 (CCK-8), colony formation, wound healing, and transwell migration/invasion assays demonstrated that TP inhibited the proliferation, migration, and invasion of SW480 and HCT116 cells in a dose-dependent manner. Bioinformatic analysis implicated glycolysis and cuproptosis in TP's anti-CRC action. Subsequent validation via glucose metabolism assays, reactive oxygen species (ROS) detection, JC-1 staining, copper ion measurement, morphological observation, qRT-PCR, and Western blotting confirmed that TP had a significant effect in both suppressing glycolysis and inducing cuproptosis in SW480 and HCT116 cells. In addition, studies have shown that TP significantly inhibits tumor growth and promotes copper accumulation within tumors. Furthermore, hematoxylin-eosin (H&E) staining and biochemical analysis have indicated that it has no obvious liver or kidney toxicity. These results suggest that TP may both inhibit the glycolysis of CRC and induce cuprotosis via the Hexokinase 2 (HK2)/Dihydrolipoamide S-acetyltransferase (DLAT) pathway. Future research should systematically verify its effectiveness and safety through studies and clinical trials to promote the application of TP in CRC treatment.