Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPβ, a rate-limiting enzyme in FAO. Although TPβ activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPβ association results in Nur77 self-sacrifice to protect TPβ from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPβ interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma.

脂肪酸氧化（FAO）通过提供ATP和NADPH对于细胞克服代谢应激至关重要。但是，粮农组织对肿瘤的调控机制仍然难以捉摸。在这里，我们表明Nur77是通过保护FAO对黑色素瘤细胞的代谢适应所必需的。葡萄糖剥夺激活ERK2磷酸化并诱导Nur77易位至线粒体，其中Nur77与TPβ（粮农组织中的限速酶）结合。尽管TPβ活性通常在葡萄糖剥夺下被氧化抑制，但Nur77-TPβ缔合会导致Nur77自我牺牲以保护TPβ免受氧化。因此，粮农组织能够维持NADPH和ATP的水平，并防止ROS升高和细胞死亡。Nur77-TPβ相互作用通过促进循环黑素瘤细胞存活进一步促进黑素瘤转移。