mTORC1-eIF4A1 dependent translational regulation of oncogenic fatty acid desaturases

Cells actively remodel their lipid composition to support membrane integrity, organelle function, and signaling as environmental and nutrient condition changes. While transcriptional control of lipogenesis has been extensively studied, how these pathways are controlled at the translational level remains incompletely defined. Our prior works identified transcriptional and post-transcriptional regulation of de novo lipogenesis. Here, we found that the mTORC1-eIF4A1 axis selectively enhances the translation of the oncogenic fatty acid desaturases stearoyl-CoA-desaturase 1 (SCD1) and fatty acid desaturase 2 (FADS2), which together supply monounsaturated fatty acids (MUFA). Across multiple mTORC1-hyperactive cancer cell lines, eIF4A1 inhibition by siRNA or small molecules (silvestrol and zotatifin) reduced the desaturase protein abundance while other lipogenic enzymes were unchanged. Using polysome assay and 5'UTR luciferase assays, we confirmed that the translational regulation is via their unique 5'UTR structures. In addition, to investigate how eIF4A1 perturbation affects cellular lipidome, we applied 13 C-isotope tracing to examine newly synthesized fatty acids and related lipids. eIF4A1 inhibition lowered cellular MUFA content, shifted phospholipids toward more saturated fatty acids and induced ER stress and lipid peroxidation. This impaired fatty acid balance and lipid composition led to decreased cell proliferation upon eIF4A1 inhibition and was partially rescued by MUFA supplementation. Extending these findings in vivo, zotatifin treatment in a Tsc2 +/- kidney tumor mouse model, where loss of Tsc2 hyperactivates mTORC1, reduced tumor burden, decreased desaturase expression, and increased lipid peroxidation. Together, these data establish a direct link between translational control and fatty acid desaturation in cancer cells, and support eIF4A1-targeted strategies to simultaneously suppress two oncogenic fatty acid desaturases in mTORC1-hyperactive tumors.