By analyzing clinical data and tumor organoid models, we revealed for the first time that p53 is located in triglyceride‐induced LDs and further clarified the mechanism by which LDs promote the MDM2‐mediated ubiquitination of p53 via the complex of p53 and Myh9, which is recruited to LDs by Cyb5r3. This evidence concerns the gene MYH9 and neoplasm.