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 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 diet 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.

Authors

Institutions

Publication Details

Journal
Cell Reports
Published
2025-10-29
DOI
https://doi.org/10.1016/j.celrep.2025.116466
Citations
1
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
0.81
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Energy status orchestrates YTHDF1 phase separation and tumorigenesis

Chuan He, Jie Shi, Wenjun Xiong, Yishuang Sun et al.
1 citations
Cell Reports
Glycosylation and Glycoproteins Research
0.81
article

Energy status orchestrates YTHDF1 phase separation and tumorigenesis

Chuan He, Jie Shi, Wenjun Xiong, Yishuang Sun, Shuchao Ren, Rong‐Rong He, Zongbi Yi, Qiushi Chen, Haisheng Yu, H. Li, Xue Zhang, Yan Ren, Jinfang Zhang, Gaoshan Xu, Zhipeng Zhou, Wenjing Song, Xiyong Wang, Yingmeng Yao, Xixin Xing
article en
1 citations

Abstract

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 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 diet 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.

Cell ReportsVol. 44(11)
Huazhong Agricultural University (CN), Wuhan University (CN), Shanghai University of Traditional Chinese Medicine (CN), Zhongnan Hospital of Wuhan University (CN), State Key Laboratory of Synthetic Chemistry (CN), University of Hong Kong (HK)
Openalex Percentile: Top 22%
Glycosylation and Glycoproteins Research
0.81
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.