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Peer-reviewedCC BY 4.0Advanced Science

Modification‐Selective Inhibition of Succinate Dehydrogenase a Enables Tumor‐Restricted Mitochondrial Modulation

  • Kaikai Xu1
  • Lulu Kong1
  • Kebin Ye1
  • Xinlu Bao1
  • Haowen Liu1
  • Ning Wang2
  • Yongming Deng3
  • Wei Wang4
  • Shaohua Wei1
  • Lin Zhou1
4 affiliations
  1. 1College of Chemistry and Materials Science Jiangsu Key Laboratory of Bio‐functional Materials Jiangsu Collaborative Innovation Centre of Biomedical Functional Materials Nanjing Normal University Nanjing China
  2. 2School of Science Key Laboratory of High Performance Scientific Computation Xihua University Chengdu China
  3. 3Department of Urology Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical School Institute of Urology Nanjing University Nanjing China
  4. 4School of Chemistry and Chemical Engineering Yancheng Institute of Technology Yancheng China
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Abstract

Succinate dehydrogenase (SDH, complex II) connects the tricarboxylic acid (TCA) cycle to the electron transport chain (ETC), maintaining mitochondrial energy homeostasis. Selective SDH inhibition in diseased tissue has remained challenging due to the highly conserved catalytic architecture across normal tissues. Here, we reveal that SDH catalytic activity depends on the acetylation state of its catalytic subunit A (SDHA): the non‐acetylated form is catalytically active but exhibits fragile homeostasis in bladder cancer, contrasting with its robust maintenance in normal cells. Guided by this insight, we designed ZPI‐3, a conformationally optimized inhibitor that selectively engages the non‐acetylated SDHA, suppressing tumor SDH activity and growth while sparing normal cells. In orthotopic NMIBC models, ZPI‐3 outperforms mitomycin‐C. Differential SDH responses to ZPI‐3 in clinical specimens further suggest its potential for patient stratification and precision therapy. These findings establish modification‐selective inhibition as a paradigm for tumor‐selective mitochondrial modulation.

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Cite

BibTeXRIS
BibTeX
@article{xu2026modificationselective,
  title = {{Modification‐Selective Inhibition of Succinate Dehydrogenase a Enables Tumor‐Restricted Mitochondrial Modulation}},
  author = {Kaikai Xu and Lulu Kong and Kebin Ye and Xinlu Bao and Haowen Liu and Ning Wang and Yongming Deng and Wei Wang and Shaohua Wei and Lin Zhou},
  journal = {Advanced Science},
  year = {2026},
  month = aug,
  doi = {10.1002/advs.77046},
  url = {https://doi.org/10.1002/advs.77046},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Modification‐Selective Inhibition of Succinate Dehydrogenase a Enables Tumor‐Restricted Mitochondrial Modulation
AU  - Kaikai Xu
AU  - Lulu Kong
AU  - Kebin Ye
AU  - Xinlu Bao
AU  - Haowen Liu
AU  - Ning Wang
AU  - Yongming Deng
AU  - Wei Wang
AU  - Shaohua Wei
AU  - Lin Zhou
PY  - 2026
DA  - 2026/08/19
JO  - Advanced Science
DO  - 10.1002/advs.77046
UR  - https://doi.org/10.1002/advs.77046
AB  - Succinate dehydrogenase (SDH, complex II) connects the tricarboxylic acid (TCA) cycle to the electron transport chain (ETC), maintaining mitochondrial energy homeostasis. Selective SDH inhibition in diseased tissue has remained challenging due to the highly conserved catalytic architecture across normal tissues. Here, we reveal that SDH catalytic activity depends on the acetylation state of its catalytic subunit A (SDHA): the non‐acetylated form is catalytically active but exhibits fragile homeostasis in bladder cancer, contrasting with its robust maintenance in normal cells. Guided by this insight, we designed ZPI‐3, a conformationally optimized inhibitor that selectively engages the non‐acetylated SDHA, suppressing tumor SDH activity and growth while sparing normal cells. In orthotopic NMIBC models, ZPI‐3 outperforms mitomycin‐C. Differential SDH responses to ZPI‐3 in clinical specimens further suggest its potential for patient stratification and precision therapy. These findings establish modification‐selective inhibition as a paradigm for tumor‐selective mitochondrial modulation.
SN  - 2198-3844
ER  -