ACOT7与“USP39-GPX4信号轴”协同调节“脂质代谢-铁死亡”稳态影响甲状腺未分化癌发生发展的机制研究

分化型甲状腺癌去分化恶性演变是ATC发生的主要因素，前期通过高通量转录组测序分析了甲状腺癌去分化的基因表达谱特征，发现脂质代谢分子ACOT7在NT→PTC→ATC进程中表达逐渐升高，潜在调控ATC的发生发展。前期文章发表及实验提示：①ACOT7在ATC中高表达提示不良预后；②ACOT7可以上调细胞内多不饱和脂肪酸的含量，调控脂肪酸和能量代谢；③ACOT7上调增加多不饱和脂肪酸过氧化；④ACOT7通过USP39，上调GPX4转录，清除脂质过氧化物，抑制铁死亡。因此提出ACOT7协同“USP39-GPX4”信号轴，增加脂质和能量代谢促进ATC发生发展，同时抑制脂质过氧化导致的氧化损伤及铁死亡，调控“脂质代谢-铁死亡”稳态，促进ATC发生发展。本次研究拟探讨ACOT7与“USP39-GPX4”的调控关系及其在脂质代谢、铁死亡中的作用，旨在逆转ATC去分化以及抑制其恶性潜能。

It is well acknowledged that ATC developed from dedifferentiation of differentiated thyroid cancer. By using high-throughput whole transcriptome to identify gene signatures in controlling the dedifferentiation process, we demonstrated that lipid metabolism gene ACOT7 increased in the dedifferentiation process. Our previous publication records and research results demonstrated that: ①High ACOT7 expression indicates an unfavorable prognosis of ATC patients; ②ACOT7 increased the contents of polyunsaturated fatty acids in ATC cells, and provides nutrients and energies that are required for maintaining malignancies of ATC cells; ③ACOT7 promotes lipid peroxidation in ATC cells; ④ ACOT7 regulates GPX4 expression via nuclear protein USP39, and increased GPX4 expression catalyzed the reduction of lipid hydroperoxides and suppressed ferroptosis. Therefore, we put forward the hypothesis that ACOT7 cooperates with “USP39-GPX4” axis in regulating lipid and energy metabolism, meanwhile detoxifies lipid hydroperoxides generated by polyunsaturated fatty acids oxidation, leading to a homeostasis of “Lipid metabolism-Ferroptosis”. The present proposal aims to regulate the regulatory cascade of ACOT7 and “USP39-GPX4” axis. Moreover, we aim to examine the effect of AOCT7、USP39 and GPX4 in regulating lipid and energy metabolism and uncover the roles of ACOT7 in suppressing ferroptosis, in the hope of reversing dedifferentiation process and inhibit malignancies of the ATC cells.