Energy status orchestrates YTHDF1 phase separation and tumorigenesis

Aberrant energy status impacts the initiation and progression of tumorigenesis, although the underlying mechanisms remain poorly understood. Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a key sensor of cellular energy stress, is activated to facilitate metabolic adaptation and regulate tumorigenesis. Here, we reveal that energy deprivation-induced activation of AMPK phosphorylates YTHDF1 at Ser198, counteracting its O-GlcNAcylation. This phosphorylation alters the functional properties of YTHDF1 by suppressing its phase separation and its interaction with the translation initiation factor eIF3b, ultimately reducing protein translation. Notably, enhancing YTHDF1 phosphorylation to antagonize its O-GlcNAcylation through AMPK agonists or ketogenic diets (KD) effectively inhibits tumor cell growth both in vitro and in vivo. These findings elucidate a regulatory mechanism that links cellular energy status to YTHDF1 post-translational modifications and highlight the therapeutic potential of targeting YTHDF1-mediated pathways via metabolic interventions for cancer treatment.异常能量状态可影响肿瘤发生的启动与进展，但其潜在分子机制仍未完全阐明。一磷酸腺苷（adenosine monophosphate, AMP）活化蛋白激酶（AMP-activated protein kinase, AMPK）作为细胞能量应激的关键感受器，激活后可促进代谢适应并调控肿瘤发生过程。本研究揭示，能量剥夺诱导的AMPK活化会在丝氨酸198（Ser198）位点磷酸化YTHDF1，进而拮抗其O-连接N-乙酰葡糖胺修饰（O-GlcNAcylation）。该磷酸化修饰通过抑制YTHDF1的相分离及其与翻译起始因子eIF3b的相互作用，改变其功能特性，最终降低蛋白质翻译效率。值得注意的是，通过AMPK激动剂或生酮饮食（ketogenic diets, KD）增强YTHDF1的磷酸化以拮抗其O-连接N-乙酰葡糖胺修饰，可在体外及体内有效抑制肿瘤细胞的增殖与生长。本研究阐明了一条将细胞能量状态与YTHDF1翻译后修饰相联系的调控机制，并凸显了通过代谢干预靶向YTHDF1介导的通路以开展癌症治疗的潜在价值。