2. Academic Validation
  3. Dihydroartemisinin Induces Ferroptosis in Uveal Melanoma Cells Through the HO-1 and xCT/GPX4 Signaling Pathways

Dihydroartemisinin Induces Ferroptosis in Uveal Melanoma Cells Through the HO-1 and xCT/GPX4 Signaling Pathways

  • Int J Mol Sci. 2026 Mar 26;27(7):3027. doi: 10.3390/ijms27073027.
Yuxuan Zhao 1 2,  Chen Hou 2 3,  Lirong Xiao 1 2,  Longqian Liu 2,  Naihong Yan 1 2
Affiliations

Affiliations

  • 1 Research Laboratory of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 41977217 DOI: 10.3390/ijms27073027
Abstract

Uveal melanoma (UM) represents an uncommon intraocular malignancy with high aggressiveness. Dysregulation of Ferroptosis has been associated with UM progression. Dihydroartemisinin (DHA), a natural derivative of Artemisia annua, exhibits potent antitumor activity with a favorable safety profile, yet its role in Ferroptosis regulation in UM remains unclear. Here, we showed that DHA significantly reduced the proliferation and invasiveness of UM cells-both primary and secondary-with effects intensifying over time and dose. Transcriptomic analysis indicated that DHA may exert antitumor effects by modulating the ferroptosis-related pathway, characterized by upregulating heme oxygenase-1 (HO-1) and downregulating the SLC7A11 (xCT)/GPX4 axis, leading to iron accumulation, increased ROS and lipid peroxidation, and mitochondrial dysfunction. Iron chelators and pancaspase inhibitors partially reverse these effects, whereas HO-1 inducers enhance them. Overall, our results suggest that DHA suppresses UM progression by inducing Ferroptosis and mitochondrial dysfunction, while the HO-1 and xCT/GPX4 pathways may contribute to these effects. DHA may represent a potential therapeutic approach for UM, warranting further investigation.

Keywords

ferroptosis; heme oxygenase 1; natural product; uveal melanoma.

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