VITAMIN E succinate (VES), a widely used dietary supplement, has been identified as a potent degrader of the m6A RNA demethylase fat mass and obesity-associated protein (FTO), which is frequently overexpressed in various cancers. This discovery highlights a novel approach to targeting FTO for cancer therapy by leveraging its degradation mechanisms. FTO plays a critical role in tumour progression and resistance to immunotherapy, making it a promising therapeutic target. The mechanism by which VES induces FTO degradation involves its interaction with both FTO and its E3 ligase DTX2, leading to increased ubiquitination and subsequent proteasomal degradation. This process disrupts FTO’s function and alters RNA methylation patterns in tumour cells.
FTO degradation by VES enhances the tumour-intrinsic immune response and increases T cell cytotoxicity, thereby improving the effectiveness of immunotherapy. In mouse models, the depletion of FTO—either genetically or through VES treatment—suppressed tumour growth and sensitised tumours to immune checkpoint blockade. Mechanistically, VES treatment led to increased m6A methylation in the Leukemia Inhibitory Factor (LIF) gene, which in turn decreased LIF mRNA decay and enhanced T cell-mediated cytotoxicity in melanoma cells. These findings underscore the significance of FTO in regulating tumour immunity and suggest that its degradation could be a viable strategy for overcoming immunotherapy resistance.
The identification of VES as a dietary degrader of FTO provides a foundation for developing more potent and specific FTO-targeting therapies. Given its established safety profile as a vitamin E derivative, VES presents an attractive option for repurposing in cancer treatment. Future research could focus on optimising VES analogues to enhance their specificity and efficacy in targeting FTO. By elucidating the molecular mechanisms underlying FTO degradation, this study paves the way for novel therapeutic strategies aimed at improving cancer treatment outcomes. The ability to pharmacologically degrade FTO represents a promising avenue for enhancing anti-tumour immunity and sensitising resistant tumours to immunotherapy, offering new hope for patients with aggressive cancers.
Katie Wright, EMJ
Reference
Gong H et al. Association between life’s crucial 9 and overactive bladder: the mediating role of weight-adjusted-waist index. Front Nutr. 2025;11:1508062.
