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USP30 senses serine/glycine levels to regulate serine biosynthesis and colorectal tumorigenesis by deubiquitinating FTO

Cell Death & Differentiation (2026)Cite this article

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Abstract

Our previous studies demonstrated that the fat mass and obesity-associated protein (FTO) is upregulated in colorectal cancer (CRC). It demethylates G6PD/PARP1 and SLC7A11/GPX4 mRNAs, thereby protecting CRC from DNA damage and ferroptotic cell death. However, the mechanisms underlying FTO upregulation in CRC remain unclear. Unexpectedly, we show Ubiquitin-specific peptidase 30 (USP30) binds serine/glycine and senses their levels to protect FTO from proteosome degradation. Stabilized FTO demethylates 3-phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1) mRNAs and inhibits their degradation in an m6A-YTHDF2-dependent manner, thereby promoting serine synthesis and CRC tumor growth. Furthermore, we identify sodium 2, 2-dichloroacetate (DCA) as a novel inhibitor of USP30, and DCA inhibits CRC serine synthesis and tumor growth. Clinically, USP30, FTO, PHGDH, and PSAT1 levels are highly correlated in CRC tissues. This study provides mechanistic insights into how USP30 senses serine/glycine levels to regulate serine synthesis via the FTO-PHGDH/PSAT1 axis, offering a potential therapeutic strategy for targeting serine/glycine metabolism in cancer.

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Fig. 1: USP30 interacts with FTO.
Fig. 2: USP30 increases FTO protein level by inhibiting deubiquitination mediated degradation in CRC cells.
Fig. 3: USP30 and FTO promote CRC cell growth by regulating PHGDH and PSAT1.
Fig. 4: USP30 and FTO enhance PHGDH and PSAT1 mRNA expression through FTO-mediated m6A modification.
Fig. 5: USP30 promotes CRC tumorigenesis through FTO-PHGDH/PSAT1 axis.
Fig. 6: Serine biosynthetic pathway activated in CRC cells under starvation.
Fig. 7: Identification of DCA as a novel inhibitor of USP30 and regulates CRC serine/glycine synthesis.
Fig. 8: DCA regulates CRC tumor growth.
Fig. 9: USP30 binds serine/glycine, senses its levels to deubiquitinate and stabilizes FTO, thereby promoting serine biosynthesis and driving colorectal cancer development tumorigenesis.

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Data availability

Raw sequencing data have been deposited at the NCBI Sequence Read Archive and are publicly accessible. Other origin data, including origin image of western blot about this paper, have been deposited at Mendeley and are publicly available. Accession numbers or DOIs are listed in the key resources table. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. All the data supporting the findings of this study are available within the article and its supplemental files. Any data generated can be requested from the corresponding authors.

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Acknowledgements

We thank Guo Chen (China Pharmaceutical University, Nanjing) for sharing plasmid DNA of UPSs and Yan Chen (Shandong Normal University, Jinan) for sharing plasmid DNA of HA-Ubiquitin mutants.

Funding

This work was supported by grants from National Nature Science Foundation of China (82473806, 82373906, and 82273963), Beijing Natural Science Foundation of China (grant no. J230016), National Science and Technology Major Project (2024ZD0521203), Beijing-Tianjin-Hebei Basic Research Cooperation Project (23JCZXJC00020), China Postdoctoral Science Foundation (2023M741829), Guangdong Basic and Applied Basic Research Foundation (2022A1515111102), the Youth Innovation Talent Project of Ordinary university in Guangdong Province, China (2022KQNCX061), and Guangzhou Science and Technology Plan Project (SL2022A04J00697).

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Author notes

  1. These authors contributed equally: Yaya Qiao, Chenxi Wang, Huanle Liu, Huanran Sun.

Authors and Affiliations

  1. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China

    Yaya Qiao, Chenxi Wang, Huanle Liu, Huanran Sun, Qijun Zhang, Xintong Dai, Mingming Sun & Changliang Shan

  2. School of Integrative Medicine, State Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin, China

    Huifang Zhao & Shuai Zhang

  3. Cardiothoracic Surgery Department, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin, China

    Taoyuan Wang

  4. Department of Pathology, Characteristic Medical Center of The Chinese People’s Armed Police Force, Tianjin, China

    Tao He

  5. Guangzhou key laboratory for clinical rapid diagnosis and early warning of infectious diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China

    Zhen Li

  6. Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining, China

    Yanping Li

  7. Tumor Research Institute, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China

    Jun Xue & Chunze Zhang

  8. Department of Colorectal Surgery, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, China

    Yaya Qiao & Chunze Zhang

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Contributions

C.S., S.Z., C.Z., and Y.Q. conceived and designed the study and wrote the manuscript with comments from all authors. Y.Q., C.W., H.L., H.S., H.Z., Q.Z., X.D., M.S., T.W., and T.H. performed experiments. Z.L., Y.L., J.X. provided reagents and technical assistance. C.S., S.Z., and C.Z. wrote, reviewed, and edited the paper.

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Correspondence to Chunze Zhang, Changliang Shan or Shuai Zhang.

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Qiao, Y., Wang, C., Liu, H. et al. USP30 senses serine/glycine levels to regulate serine biosynthesis and colorectal tumorigenesis by deubiquitinating FTO. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01680-2

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