A high-fat diet (HFD) promotes metastasis through increased uptake of saturated fatty acids (SFAs). The fatty acid transporter CD36 has been implicated in this process, but a detailed understanding of CD36 function is lacking. During matrix detachment, endoplasmic reticulum (ER) stress reduces SCD1 protein, resulting in increased lipid saturation. Subsequently, CD36 is induced in a p38- and AMPK-dependent manner to promote preferential uptake of monounsaturated fatty acids (MUFAs), thereby maintaining a balance between SFAs and MUFAs. In attached cells, CD36 palmitoylation is required for MUFA uptake and protection from palmitate-induced lipotoxicity. In breast cancer mouse models, CD36-deficiency induced ER stress while diminishing the pro-metastatic effect of HFD, and only a palmitoylation-proficient CD36 rescued this effect. Finally, AMPK-deficient tumors have reduced CD36 expression and are metastatically impaired, but ectopic CD36 expression restores their metastatic potential. Our results suggest that, rather than facilitating HFD-driven tumorigenesis, CD36 plays a supportive role by preventing SFA-induced lipotoxicity.

高脂饮食 （HFD） 通过增加饱和脂肪酸 （SFA） 的摄取来促进转移。脂肪酸转运蛋白 CD36 与此过程有关，但缺乏对 CD36 功能的详细了解。在基质分离过程中，内质网 （ER） 应激会降低 SCD1 蛋白，导致脂质饱和度增加。随后，CD36 以 p38 和 AMPK 依赖性方式诱导，以促进单不饱和脂肪酸 （MUFA） 的优先摄取，从而维持 SFA 和 MUFA 之间的平衡。在贴壁细胞中，CD36 棕榈酰化是 MUFA 摄取和保护免受棕榈酸酯诱导的脂毒性所必需的。在乳腺癌小鼠模型中，CD36 缺陷诱导了 ER 应激，同时降低了 HFD 的促转移作用，只有精通棕榈酰化的 CD36 才能挽救这种作用。最后，AMPK 缺陷型肿瘤的 CD36 表达降低并受到转移性损害，但异位 CD36 表达恢复了其转移潜力。我们的结果表明，CD36 不是促进 HFD 驱动的肿瘤发生，而是通过防止 SFA 诱导的脂毒性而发挥支持作用。