Dihydroartemisinin Unravels Dose-Dependent Transcriptomic Networks Orchestrating Ferroptosis and Metabolic...

Area of Science:

• Molecular Biology
• Cancer Research
• Pharmacology

Background:

• Dihydroartemisinin (DHA), derived from *Artemisia annua*, shows promise as an anticancer agent.
• The precise dose-dependent molecular mechanisms of DHA in colorectal cancer (CRC) are not fully understood.
• Clarifying these mechanisms is crucial for optimizing DHA-based CRC therapies.

Purpose of the Study:

• To elucidate the dose-dependent transcriptional regulatory networks of DHA in human CRC cells.
• To investigate the molecular mechanisms underlying low- and high-dose DHA treatment.
• To reveal the crosstalk between biological processes affected by DHA in a dose-dependent manner.

Main Methods:

• RNA-sequencing (RNA-seq) transcriptomic profiling was performed on HCT116 cells.
• Cells were treated with either 20 μM (low-dose) or 50 μM (high-dose) DHA.
• Bioinformatic analyses included screening differentially expressed genes (DEGs) and Gene Ontology (GO) and KEGG pathway enrichment.

Main Results:

• DHA demonstrated dose-dependent inhibition of cell viability, with an IC50 of 50 μM.
• Low-dose DHA induced apoptosis via endoplasmic reticulum stress and senescence via G2/M phase arrest.
• High-dose DHA primarily modulated ferroptosis-associated gene expression by regulating iron homeostasis and lipid peroxidation, while also suppressing glycolysis, lipid, and folate metabolism.

Conclusions:

• This study identifies ferroptosis-related gene networks as critical transcriptional targets of DHA.
• A dose-dependent interplay among cell death, senescence, metabolic reprogramming, and signaling pathways was revealed.
• The findings provide a transcriptomic framework and potential gene targets for enhancing DHA efficacy in colorectal cancer treatment.