Targeting the ELAVL1-HMGCR axis disrupts lipid-droplet buffering and promotes lipotoxic cell death in colorectal cancer

Abstract Lipid metabolic reprogramming is a key feature of colorectal cancer (CRC), yet how CRC cells tolerate lipid overload and evade lipotoxic cell death remains incompletely understood. This study reveals that the ELAVL1/HMGCR/lipid-droplet axis supports CRC cell survival under lipid-rich conditions. Fatty-acid exposure, high-fat diet, and tumor-associated metabolic remodeling promoted cytoplasmic translocation of the RNA-binding protein ELAVL1, accompanied by lipid droplet accumulation in CRC. ELAVL1 depletion impaired triglyceride and cholesterol ester storage, reduced lipid-droplet biogenesis, and sensitized CRC cells to endoplasmic reticulum stress, mitochondrial fragmentation, membrane damage, reactive oxygen species accumulation, and apoptosis. Conversely, ELAVL1 overexpression enhanced neutral-lipid storage and protected cells from lipotoxic damage. Mechanistically, ELAVL1 binds the 3′UTR of HMGCR mRNA and enhances its stability, thereby maintaining the cholesterol/mevalonate pathway. In ELAVL1-deficient cells, restoration of HMGCR rescued lipid droplet formation, lipid homeostasis, and organelle integrity, whereas inhibition of HMGCR abolished ELAVL1-driven lipid droplet expansion and cytoprotective effects. In high-fat-diet-associated CRC models, ELAVL1 inhibition suppressed lipid-droplet accumulation, whereas combined ELAVL1/HMGCR targeting disrupted lipid homeostasis, enhanced apoptosis, and reduced tumor burden. These findings suggest that ELAVL1-mediated stabilization of HMGCR mRNA promotes lipid-droplet buffering, thereby protecting CRC cells from lipotoxic cell death, and point to a targetable vulnerability in colorectal cancer therapy.