Dig Dis Sci. 2025 Nov 8. doi: 10.1007/s10620-025-09503-z. Online ahead of print.
ABSTRACT
BACKGROUND: Liver cancer is the third most common cause of cancer-related death after lung and colorectal cancers. Hepatocellular carcinoma (LIHC) is the predominant subtype. Doxorubicin (DOX), an anthracycline chemotherapy drug, is extensively employed in the clinical treatment of early-stage and mid-stage liver cancer. Unfortunately, resistance that develops with long-term treatment severely undermines its therapeutic efficacy. Dihydroartemisinin (DHA), an antimalarial drug, has shown great potential in modulating the tumor microenvironment and inhibiting tumor growth, yet our understanding of its mechanisms remains limited.
METHODS: Network pharmacology identified CCT3 as a potential DHA target. Autodock predicted the binding of CCT3 and DHA. CCT3 expression in tumor and normal samples was analyzed using the TCGA-LIHC dataset. GSEA mapped out the pathways enriched by CCT3. qPCR and WB were used to measure CCT3 expression. Drug affinity responsive target stability assay verified the binding of CCT3 and DHA. The effects of DOX and DHA on cancer cell viability were probed using CCK-8, TUNEL, and flow cytometry. Cellular oxidative stress (OS) levels were assessed with intracellular reactive oxygen species (ROS) detection and JC-1 staining.
RESULTS: DHA and DOX both proved effective in suppressing cancer cell viability and boosting apoptosis. Their combined use further amplified these effects. CCT3 was identified as a crucial target protein for DHA in LIHC treatment, with a strong binding capacity. This protein was particularly enriched in pathways associated with OS. In DOX-resistant cells, overexpressing CCT3 remarkably heightened resistance and reduced apoptosis, which possibly stemmed from the role of CCT3 in maintaining cellular ROS and mitochondrial membrane potential homeostasis, thereby reducing OS. Notably, these effects of CCT3 could be effectively inhibited by targeting DHA.
CONCLUSION: DHA can target and inhibit CCT3 to induce OS, thereby enhancing the therapeutic efficacy of DOX.
PMID:41205108 | DOI:10.1007/s10620-025-09503-z