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Updated: Jan 10, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Novel MAFG-METTL14-SCD1 axis regulates lipid metabolism mediating choroidal melanoma distant metastasis
Xi Zhang1,2,3, Xiaoyun Hu1,2,4, Chen Fu1,2,4
1Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, P. R. China.
Background:
Tumor invasion and metastasis are strongly influenced by cell membrane fluidity, regulated by lipid metabolism. In choroidal melanoma (CM), a highly metastatic cancer, the relationship between lipid metabolism, membrane fluidity, and metastatic mechanisms remains unclear.
Methods:
We examined m6A methylation in CM patient samples. Lipidomic profiling was performed in control, METTL14-silenced, or SCD1-silenced CM cells. Transcriptomics were analyzed after METTL14 manipulation. Transmission electron microscopy assessed ultrastructural changes, while multiplex immunohistochemistry validated the clinical relevance of the MAFG-METTL14-SCD1 axis. The anti-metastatic effect of combining the SCD1 inhibitor aramchol with a stearate-rich diet (S-HFD) was tested in nude mouse CM metastasis models.
Results:
Lipidomics revealed that SCD1 promotes CM progression via cardiolipin and fatty acid metabolism pathways. Silencing SCD1 reduced membrane fluidity, while its upregulation in CM was driven by METTL14-mediated m6A methylation at the 2492 mRNA site. Elevated MAFG expression further activated METTL14. Mechanistically, this MAFG-METTL14-SCD1 axis enhanced CM invasiveness. In preclinical models, aramchol combined with S-HFD markedly suppressed distant metastasis.
Conclusions:
Our study identifies SCD1-mediated lipid remodeling as a key driver of enhanced membrane fluidity and metastatic potential in CM. Inhibition of SCD1 increases lipid saturation, reduces membrane fluidity, induces oxidative stress, and suppresses liver and lung metastasis. The MAFG-METTL14-SCD1 axis thus represents a critical regulator of CM progression, and combined therapeutic targeting with aramchol and S-HFD offers promising translational potential.
