Fig 1: p53 degradation enhances intracellular lipid accumulation by regulating the nuclear import of the RPS3A‐C/EBPβ complex. A) Gene Ontology analysis of differentially expressed genes in 4T1 cells treated with ND or HFD serum, highlighting the role of the PPAR pathway in CD36 upregulation. B) Gene Ontology analysis of differentially expressed genes in 4T1 cells treated with or without oleic acid, emphasizing the involvement of the PPAR pathway in CD36 upregulation. C) Western blot analysis of p53, CD36, and PPARγ expression in tumor cells treated with OA and TC. D) Immunoprecipitation and Western blot demonstrating the interaction between p53 and RPS3A on purified LDs from tumor cells. E,F) Fluorescence imaging staining showing the effect of p53 knockdown (shp53‐1 and shp53‐2) on the nuclear localization of RPS3A (E) and C/EBPβ (F) in OA‐treated tumor cells, G) Immunoprecipitation and Western blot analysis showing the interaction between RPS3A and C/EBPβ in tumor cells, H,I) Western blotting of nuclear and cytoplasmic fractions showing the effects of p53 knockdown (shp53‐1 and shp53‐2) (H) and RPS3A knockdown (shRPS3A‐1 and shRPS3A‐2) (I) on the cytoplasmic or nuclear localization of RPS3A and C/EBPβ in tumor cells treated with OA and TC. J) Schematic model proposing that p53 degradation leads to CD36 upregulation, allowing increased lipid droplet accumulation in tumor cells and further promoting p53 degradation, forming a positive feedback loop. Experimental conditions: tumor cells were treated with 100 µm OA or 3 µm TC. β‐actin was used as a control for Western blotting. Scale bars: 5 µm (E,F). Control: fetal bovine serum; ND: normal diet; HFD: high‐fat diet; OA: oleic acid; TC: triacsin C.