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Reversible ALKBH5 cytosolic aggregation accelerates cellular senescence

Cell Death & Differentiation volume 33, pages 171–187 (2026)Cite this article

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Abstract

Cellular senescence is the major hallmark and therapeutic target of aging and age-related diseases. The role of ALKBH5, one of the main m6A demethylases, in cellular senescence emerges however remains contentious. Herein, we show the reversible ALKBH5 aggregation in cytoplasm promotes cellular senescence. Mechanically, ALKBH5 aggregation causes cytosolic retention, resulting in the m6A dysregulation and m6A hypermethylation of Cdk2, which promotes Cdk2 RNA instability to drive senescence. In addition, m6A imbalance aggravates ALKBH5 cytosolic aggregation in a feedback loop. We further demonstrate that ALKBH5 nuclear translocation required the formation of ALKBH5 droplet phase via binding Nucleoporin p62 (Nup62), while the aggregation of ALKBH5 traps with Nup62 in the cytoplasm. Reduced Nup62 prevents ALKBH5 nuclear entry leading to cellular senescence. Importantly, administration of m6A labeled RNA efficiently reverses ALKBH5 cytosolic aggregates and restores its nuclear entry to alleviate cellular senescence. Forced nuclear entry by NLS-ALKBH5 can prevent senescence in vitro and in vivo. Taken together, these findings unravel a novel paradigm for m6A epigenetic regulation in cellular senescence and offer promising therapeutic targets and strategies for the intervention of aging and age-associated diseases.

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Fig. 1: ALKBH5 cytosolic retention promotes cellular senescence.
Fig. 2: Cytoplasmic retention of ALKBH5 causes m6A imbalance to drive senescence.
Fig. 3: m6A imbalance feedback loop aggravates ALKBH5 cytosolic aggregation to accelerate senescence.
Fig. 4: Nup62 functions as a mediator for the nuclear translocation of ALKBH5.
Fig. 5: ALKBH5 intrinsic structure orchestrates solid aggregates transition and subcellular distribution.
Fig. 6: ALKBH5 forms cytoplasmic droplets to facilitate nuclear transportation.
Fig. 7: NLS-ALKBH5 mitigates senescence-related signatures in vivo.

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Data availability

All sequencing data generated for this paper have been deposited at NCBI’s Gene Expression Omnibus under accession number GSE264231.

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Acknowledgements

We thank Dr. Ge Gao, Dr. Linsheng Wang, Dr. Deliang Zhu and Dr. Zhihong Chen for their assistance in this project. This work was supported by National Natural Science Foundation of China (81821003, 82273180 and 32300617), Guangdong Basic and Applied Basic Research Foundation (2024A1515011365, 2021B1515130004), Science and Technology Projects in Guangzhou (2025A03J4509), China Postdoctoral Science Foundation (2023T160133), Guangdong Provincial People’s Hospital, High-level Hospital Construction Project (KJ012021074, KJ012019517).

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Author notes

  1. These authors contributed equally: Liqian Chen, Zixin Chen.

Authors and Affiliations

  1. Guangdong Cardiovascular Institute, Medical Research Institute, School of Basic Medical Science, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China

    Liqian Chen, Zixin Chen, Jiahui Mo, Qingqiang Xie, Wenjie Lin, Yuxiu Zou & Guoxiang Jin

  2. School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 999077, China

    Liqian Chen, Huiling Zheng & Zhongjun Zhou

  3. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China

    Liqian Chen & Xiu-Wu Bian

  4. Department of Urology and Andrology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China

    Jiahui Mo

  5. School of Medicine South China University of Technology, Guangzhou, 510006, China

    Wenjie Lin

  6. Department of Joint Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China

    Yufan Chen

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Contributions

GJ, ZZ, X-WB and LC conceived the study. LC, ZC, JM, QX, WL, HZ, YC and YZ generated reagents and conducted experiment design and execution, data collection and data analysis. ZC and LC performed bioinformatics analysis. GJ, ZZ, X-WB, and LC wrote the manuscript.

Corresponding authors

Correspondence to Xiu-Wu Bian, Zhongjun Zhou or Guoxiang Jin.

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All procedures were performed in compliance with the relevant guidelines and regulations, as approved by the Ethics Review Committee of Guangdong Provincial People’s Hospital (KY2024-450-02).

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Chen, L., Chen, Z., Mo, J. et al. Reversible ALKBH5 cytosolic aggregation accelerates cellular senescence. Cell Death Differ 33, 171–187 (2026). https://doi.org/10.1038/s41418-025-01560-1

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