2. Academic Validation
  3. Targeting MMA-induced USP36 methylmalonylation to suppress macrophage polarization and tumor progression in clear-cell renal cell carcinoma

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

  • Cell Death Differ. 2025 Dec 15. doi: 10.1038/s41418-025-01646-w.
Daojia Miao # 1 2,  Jian Shi # 3 4,  Diaoyi Tan # 3 4,  Chuanyi Zhao # 3 4,  Qingyang Lv 3 4,  Feiyi Lu 3 4,  Junkai Yang 3 4,  Hongmei Yang 5,  Zhiyong Xiong 6 7,  Xiaoping Zhang 8 9 10
Affiliations

Affiliations

  • 1 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 2 Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 3 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China.
  • 6 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 7 Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 8 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 9 Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 10 Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China. [email protected].
  • # Contributed equally.
PMID: 41398045 DOI: 10.1038/s41418-025-01646-w
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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