2. Academic Validation
  3. SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence

SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence

  • Commun Biol. 2025 Oct 20;8(1):1485. doi: 10.1038/s42003-025-08878-z.
Zhang Xianhong # 1,  Gao Yue # 1,  Zhang Yu 1,  Zhang Yichen 1,  Chen Yufei 1,  Pei Xinke 1,  Zhang Jinhui 1,  Wang Yiqi 1,  Du Yitian 2,  Hao Shuailin 3,  Ni Ting 4 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, 010070, Hohhot, P.R. China.
  • 2 State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, 010070, Hohhot, P.R. China. yitian_du@163.com.
  • 3 State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, 010070, Hohhot, P.R. China. shuailh@imu.edu.cn.
  • 4 State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, 010070, Hohhot, P.R. China. tingni@fudan.edu.cn.
  • 5 State Key Laboratory of Genetics and Development of Complex Phenotypes, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, Center for Evolutionary Biology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, 200438, Shanghai, P.R. China. tingni@fudan.edu.cn.
  • # Contributed equally.
PMID: 41116031 DOI: 10.1038/s42003-025-08878-z
Abstract

Protein lysine succinylation is a crucial post-translational modification that regulates nearly all aspects of eukaryotic and prokaryotic cell, including gene transcription, cell metabolism and redox homeostasis. Among them, metabolic disorders caused by dysfunctional post-translational modifications induce aging and aged-related diseases, including Cancer. This study quantified the dynamic changes in protein succinylation in response to DNA damage stress induced by etoposide (ETOP) in tumor cells. A total of 4354 lysine succinylation sites on 1259 proteins were identified, many of which have not been previously reported. Bioinformatics analysis revealed that many proteins are involved in the metabolism of nicotinamide adenine dinucleotide phosphate (NADPH) in mitochondria (including MTHFD2). We further found that low activity or depletion of MTHFD2 enhances the degree of TIS in breast Cancer cells and decreases their resistance to chemotherapeutic agents. Interestingly, we also found that SIRT5-mediated desuccinylation of MTHFD2 was able to reduce the senescence of breast Cancer cells, thereby enhancing their resistance to chemotherapeutic drugs. This effect may explain the poorer prognosis observed in breast Cancer patients with high expression levels of SIRT5 or MTHFD2. These systematic analyses provide new insights into targeting succinylation-modified metabolic proteins to enhance TIS, and their combination with senolytics for breast Cancer therapy.

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