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Targeting MMA-induced USP36 methylmalonylation to suppress macrophage polarization and tumor progression in

Daojia Miao1,2, Jian Shi3,4, Diaoyi Tan3,4

  • 1Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. miaodj@hust.edu.cn.

Cell Death and Differentiation
|December 15, 2025
PubMed

Insights

Elevated methylmalonic acid (MMA) in clear-cell renal cell carcinoma (ccRCC) fuels tumor growth by activating Hedgehog signaling. Lowering MMA via diet or MC3138 inhibits tumor progression and macrophage polarization.

Area of Science:

  • Oncology
  • Metabolism
  • Immunology

Background:

  • Metabolic reprogramming is a key feature of clear-cell renal cell carcinoma (ccRCC).
  • Understanding metabolic dysregulation in ccRCC is crucial for identifying new therapeutic targets.
  • The tumor microenvironment (TME) is significantly altered by metabolic changes in ccRCC.

Purpose of the Study:

  • To investigate the role of metabolic dysregulation in ccRCC pathogenesis.
  • To identify novel therapeutic targets for ccRCC based on metabolic alterations.
  • To elucidate the mechanism by which methylmalonic acid (MMA) influences the TME and tumor progression.

Main Methods:

  • Metabolomic profiling to identify metabolic alterations in ccRCC.
  • Investigating the interaction between MMA, SUFU, and Hedgehog signaling pathway.
  • In vitro and in vivo experiments to assess the efficacy of dietary intervention and MC3138 treatment.

Main Results:

  • Elevated MMA levels were identified in ccRCC, linked to reduced methylmalonyl-CoA mutase (MMUT) activity.
  • MMA activates the SUFU-regulated Hedgehog signaling pathway, promoting M2 macrophage polarization and tumor progression.
  • MMA induces methylmalonylation of USP36, inhibiting SUFU deubiquitination and promoting GLI1 expression.
  • A low branched-chain amino acids (BCAAs) diet and MC3138 treatment inhibited M2 macrophage polarization and tumor progression.

Conclusions:

  • MMA plays a critical role in ccRCC pathogenesis by modulating the tumor microenvironment and promoting tumor progression.
  • Targeting MMA accumulation and its downstream signaling pathways presents a potential therapeutic strategy for ccRCC.
  • Combining a low-BCAAs diet with MC3138 therapy may be a promising treatment approach for ccRCC patients with elevated MMA levels.

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