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PRMT5 K240lac confers ferroptosis resistance via ALKBH5/SLC7A11 axis in colorectal cancer

Oncogene (2025)Cite this article

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Abstract

Ferroptosis is a newly discovered type of regulated cell death, characterized by the iron-dependent accumulation of lipid reactive oxygen species, which has been implicated in a number of human diseases. However, the regulatory mechanisms underlying ferroptosis in colorectal cancer (CRC) remain unclear. In this study, we unravel the pivotal role of PRMT5 in the progression of CRC by promoting ferroptosis resistance. Mechanistically, PRMT5 directly inhibits the transcription of m6A demethylase ALKBH5 via histone modifications (H4R3me2s and H3R8me2s), bolstering SLC7A11 mRNA stability and expression, thereby aggravating CRC progression through attenuating ferroptosis. Particularly, our work identifies PRMT5 as a novel lactylation substrate at lysine 240 (PRMT5 K240lac), crucial for sustaining CRC ferroptosis resistance by shaping the ALKBH5/SLC7A11 axis, while mutation disrupting these effects. Overall, our work underscores the significance of PRMT5 K240lac in conferring ferroptosis resistance in CRC, proposing targeted intervention along the PRMT5 K240lac/ALKBH5/SLC7A11 axis as an innovative therapeutic approach in CRC treatment.

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Fig. 1: PRMT5 is required for the proliferation of CRC cells and negatively associated with ferroptosis in CRC.
Fig. 2: Knockdown of PRMT5 promotes ferroptosis in vitro and in vivo.
Fig. 3: PRMT5 facilitates the expression of SLC7A11 in CRC cells.
Fig. 4: PRMT5 upregulates the expression of SLC7A11 through transcriptionally inhibiting the expression of ALKBH5.
Fig. 5: PRMT5 is lactylated at K240 in CRC.
Fig. 6: K240lac is essential for PRMT5 to modulate ALKBH5/SLC7A11 axis.
Fig. 7: PRMT5 K240R sensitizes CRC cells to ferroptosis.

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Data availability

The datasets used in the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the Talent Construction Fund Research Project of Jiangsu Province Geriatric Hospital (Grant No. IR2024103), the Research Incubation Startup Fund of Jiangsu Province Geriatric Hospital (Grant No. FHQD202502), the Natural Science Foundation of Jiangsu Province (Grant No. BK202402101, BK20231261, BK20241997, BK20241998), the Jiangsu Primary Research & Development Plan (Grant No. BE2021747) and the Medical scientific research project of Jiangsu Provincial Commission of Health (Grant No. H2023048).

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Author notes

  1. These authors contributed equally: Shuang Qu, Baijie Feng, Mengying Xing, Yingyi Qiu, Longjun Ma.

Authors and Affiliations

  1. Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Shuang Qu & Shouyong Gu

  2. Department of Medical Oncology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China

    Baijie Feng

  3. The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China

    Mengying Xing

  4. National Experimental Teaching Center of Basic Medical Science, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China

    Yingyi Qiu, Feng Huang, Yuanrong Wang, Jingwan Zhou, Jiaxin He, Qinyao Zhou, Xin Zhou, Wenjing Xiong & Bing Yao

  5. Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China

    Longjun Ma, Min Xu & Shouyong Gu

  6. Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

    Zhou Yang

  7. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China

    Yi Ji & Ming Liu

  8. The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China

    Ming Liu

  9. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Qiantong Dong

  10. Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China

    Liu Yang

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  1. Shuang Qu
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Contributions

ML, QD, LY, and SG provided the study concept and design. BY, ZY, and MX wrote the manuscript. SQ, BF, MX, YQ, LM, YJ, FH, JZ, MX, and JH performed the experiments. QZ and XZ interpreted and analyzed the data. YW and WX collected the patients’ samples. YJ, SG, BY, and ML provided financial support. ML, QD, LY, and SG is responsible for the overall content as the guarantor and supervised the project. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Ming Liu, Qiantong Dong, Liu Yang or Shouyong Gu.

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The authors declare no competing interests.

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Written informed consent was obtained from all patients and the study was approved by the Ethics Committee of Jiangsu Province Geriatric Hospital. Animal experiments were performed according to the Health Guide for the Care and Use of Laboratory Animals approved by the Animal Experimental Research Ethics Committee of Jiangsu Province Geriatric Hospital.

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Qu, S., Feng, B., Xing, M. et al. PRMT5 K240lac confers ferroptosis resistance via ALKBH5/SLC7A11 axis in colorectal cancer. Oncogene (2025). https://doi.org/10.1038/s41388-025-03457-2

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