2. Academic Validation
  3. MDH2 regulates the sensitivity of clear cell renal cell carcinoma to ferroptosis through its interaction with FSP1

MDH2 regulates the sensitivity of clear cell renal cell carcinoma to ferroptosis through its interaction with FSP1

  • Cell Death Discov. 2024 Aug 13;10(1):363. doi: 10.1038/s41420-024-02137-6.
Baijie Feng # 1,  Wei Su # 2,  Xianzhi Guo 1,  Tingting Ding 1,  Yingchun Duan 3,  Lina Hu 4,  Minghua Yu 5
Affiliations

Affiliations

  • 1 Fudan University Clinical Research Center for Cell-based Immunotherapy & Department of Oncology, Fudan University Pudong Medical Center, Shanghai, P. R. China.
  • 2 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 3 Department of Gynecology and Obstetrics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, P. R. China.
  • 4 Fudan University Clinical Research Center for Cell-based Immunotherapy & Department of Oncology, Fudan University Pudong Medical Center, Shanghai, P. R. China. smilehln@163.com.
  • 5 Fudan University Clinical Research Center for Cell-based Immunotherapy & Department of Oncology, Fudan University Pudong Medical Center, Shanghai, P. R. China. minghua_md@fudan.edu.cn.
  • # Contributed equally.
PMID: 39138167 DOI: 10.1038/s41420-024-02137-6
Abstract

Malate dehydrogenase 2 is a pivotal Enzyme in the tricarboxylic acid cycle. Recent studies have highlighted the significant involvement of MDH2 in the pathogenesis and progression of diverse types of tumors, yet its precise mechanistic underpinnings remain elusive. This study revealed a significant decrease in MDH2 expression in renal Cancer tissues. And knocking out MDH2 was observed to hinder the proliferation of normal renal tubular epithelial cells but notably enhance the proliferation of ccRCC. Furthermore, mechanistically, we found that MDH2 inhibits the proliferation of ccRCC by promoting Ferroptosis, while enhancing the sensitivity of ccRCC to Ferroptosis inducers, promoting lipid peroxidation. We also demonstrated that MDH2 regulates the ubiquitination of FSP1 through protein-protein interactions, leading to a decrease in FSP1 protein levels and maintaining high sensitivity of ccRCC to Ferroptosis. In conclusion, our study demonstrates that the reduced MDH2 expression in ccRCC results in increased expression of FSP1, thereby reducing its sensitivity to Ferroptosis. It unveils a non-metabolic role for the downregulation of MDH2 in ccRCC progression.

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