MTHFD2促进GCLM-GSH和NAD(P)H-CoQ10H2介导未分化甲状腺癌铁死亡抵抗作用及机制研究

未分化甲状腺癌（ATC）是恶性程度最高的甲状腺癌，尚无有效治疗方案。诱导铁死亡近年被认为是极具潜力的抗癌新策略之一，在ATC领域的研究仍一片空白。项目组前期多组学结合临床标本证实MTHFD2在ATC中高表达；敲减MTHFD2抑制ATC细胞活性，诱导ROS，减少GSH/GSSG和NADPH/NADP+比率，并显著增加其对铁死亡诱导剂的敏感性；该效应可能与MTHFD2稳定GCLM表达，及促进氧化型CoQ10向还原型CoQ10H2转换有关。基于此，本项目拟在临床、分子细胞及动物水平展开研究，包括：MTHFD2促进ATC恶性进展的作用；MTHFD2稳定GCLM促进GSH合成，及促进NAD(P)H产生以促使CoQ10向CoQ10H2转换在ATC铁死亡抵抗中的作用机制。预期将阐明MTHFD2促进ATC恶性进展的作用，揭示其介导ATC铁死亡抵抗的全新作用机制，为ATC治疗提供新靶点和联合靶向策略。

Anaplastic thyroid cancer (ATC) is the most advanced and aggressive thyroid cancer and there is no effective treatment for this disease. Targeting ferroptosis has been considered as a promising anticancer strategy, whereas still the relative research in ATC is blank at present. Using multiple human anaplastic thyroid cancer sequence data sets combined with clinical specimens and cell lines, we confirmed that MTHFD2 was most highly expressed in ATC; Knocking down of MTHFD2 significantly inhibited ATC cell viabilities, induced ROS, decreased ratio of GSH/GSSG and NADPH/NADP+, and significantly increased its sensitivity to ferroptosis inducers, which may be associate with MTHFD2 stabilizing GCLM, as well as facilitating CoQ10/CoQ10H2 conversion. Based on this, we focus on clinical, molecular, cellular and animal levels to validate the roles of MTHFD2 in ATC and ferroptosis resistance: the oncogenic role of MTHFD2 in promoting malignant progress of ATC; the role and mechanism of MTHFD2 in stabilizing GCLM to promote GSH synthesis, as well as increasing NAD(P)H production to promote CoQ10/CoQ10H2 conversion in ferroptosis resistance of ATC. Expectedly, this project will clarify the critical role of MTHFD2 in promoting the malignant progression of ATC, reveal a new action and mechanism of MTHFD2 to mediate ferroptosis resistance in ATC, and provide a potential target and strategy for ATC treatment.