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Targeting MMA-induced USP36 methylmalonylation to suppress macrophage polarization and tumor progression in clear-cell renal cell carcinoma

Cell Death & Differentiation (2025)Cite this article

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Abstract

Metabolic reprogramming is a hallmark of clear-cell renal cell carcinoma (ccRCC), driving tumor progression and altering the tumor microenvironment (TME), making it crucial to understand metabolic dysregulation in ccRCC and to identify new therapeutic targets for patients. In this study, metabolomic profiling identified elevated levels of methylmalonic acid (MMA) in ccRCC, attributed to downregulation of methylmalonyl-CoA mutase (MMUT). MMA produced by ccRCC accumulates in the TME and activates the suppressor of fused (SUFU)-regulated Hedgehog signaling pathway in a dose-dependent manner, promoting M2 polarization of macrophages and tumor progression. Mechanistically, MMA induces methylmalonylation at the K499 site of ubiquitin-specific peptidase 36 (USP36), inhibiting USP36-mediated deubiquitination and SUMOylation of SUFU, thereby promoting the expression of GLI family zinc finger 1 (GLI1) and its target genes. Both in vitro and in vivo experiments demonstrated that a low branched-chain amino acids (BCAAs) diet or treatment with the de-methylmalonylation agent MC3138 effectively inhibited M2 polarization of macrophages and tumor progression. These findings emphasize the critical role of MMA in ccRCC pathogenesis and suggest that combining a low-BCAAs diet with MC3138 therapy may offer a promising treatment strategy for ccRCC patients with elevated MMA levels.

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Fig. 1: MMA accumulated in ccRCC and MMUT downregulation was the point of increased MMA levels.
Fig. 2: MMA promoted tumor progression in ccRCC.
Fig. 3: MMA-induced M2-macrophage promoted tumor progression in ccRCC.
Fig. 4: MMA promoted tumor progression and M2 polarization of macrophage by the Hedgehog signaling pathway.
Fig. 5: MMA-induced methylmalonylation of USP36 activated the Hedgehog signaling pathway.
Fig. 6: USP36 regulated the Hedgehog signaling pathway by disrupting the balance between ubiquitination and SUMOylation of SUFU.
Fig. 7: Combination of low-BCAAs diet and MC3138 suppressed tumor progression and macrophage M2 polarization in ccRCC.
Fig. 8: The mechanism scheme of MMA in ccRCC.

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Data availability

The datasets generated and analyzed during the current study are available in NHANES database (https://www.cdc.gov/nchs/nhanes/index.htm), TCGA-KIRC database (https://portal.gdc.cancer.gov), ICGC-RECA database (https://dcc.icgc.org/), and CPTAC3 database (https://registry.opendata.aws/cptac-3). The sequencing datasets from RNA-seq, Unbiased-broad-spectrum metabolomics have been deposited in Science Data Bank (https://www.scidb.cn/s/UZnqaq). The MS datasets have been also deposited in Science Data Bank (https://www.scidb.cn/s/UZnqaq). Other data generated in this study are available upon request from the corresponding author.

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Funding

This study was supported by the National Natural Science Foundation of China (82202911, 82300786), Shenzhen Medical Research Fund (B2302054) and Postdoctoral Fellowship Program and China Postdoctoral Science Foundation (BX20250229).

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  1. These authors contributed equally: Daojia Miao, Jian Shi, Diaoyi Tan, Chuanyi Zhao.

Authors and Affiliations

  1. Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Daojia Miao, Jian Shi, Diaoyi Tan, Chuanyi Zhao, Qingyang Lv, Feiyi Lu, Junkai Yang, Zhiyong Xiong & Xiaoping Zhang

  2. Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Daojia Miao, Jian Shi, Diaoyi Tan, Chuanyi Zhao, Qingyang Lv, Feiyi Lu, Junkai Yang, Zhiyong Xiong & Xiaoping Zhang

  3. Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China

    Hongmei Yang

  4. Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China

    Xiaoping Zhang

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Contributions

ZXP, XZY, and MDJ designed and directed data processing procedures. MDJ, SJ, TDY, ZCY, LQY, LFY, YJK, and YHM analyzed the data. MDJ wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Daojia Miao, Zhiyong Xiong or Xiaoping Zhang.

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This study was approved by the Institutional Review Board of Huazhong University of Science and Technology. The license number of the ethical review for the study is S3693. All methods were performed in accordance with the relevant guidelines and regulations.

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Miao, D., Shi, J., Tan, D. et al. Targeting MMA-induced USP36 methylmalonylation to suppress macrophage polarization and tumor progression in clear-cell renal cell carcinoma. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01646-w

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