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Peer-reviewedCC BY 4.0Advanced Science

Mepce Restrains Ferroptosis in Prostate Cancer Through 7SK–P‐TEFb Pause Control

  • Tongtong Zhang1,2,3,4,5
  • Xiangyang Zhan1,2,3,4
  • Jiexiang Zhang1,2,3,4
  • Mingyue Tan1,2,3,4
  • Chuanmin Chu1,2,3,4
  • Guanqun Ju1,2,3,4
  • Xinyu Zhai1,2,3,4
  • Jianyi Gu1,2,3,4
  • Huirong Zhu5
  • Dongliang Xu1,2,3,4
5 affiliations
  1. 1Urology Centre Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai China
  2. 2Surgical Institute of Integrative Medicine Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai China
  3. 3Surgical Institute Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai China
  4. 4Shanghai Key Laboratory of Traditional Chinese Clinical Medicine Shanghai China
  5. 5Department of Medical Oncology Shuguang Hospital Shanghai University of Traditional Chinese Medicine Shanghai China
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Abstract

Ferroptosis can be therapeutically induced through GPX4 inhibition, but the mechanisms that determine ferroptosis sensitivity in prostate cancer remain incompletely understood. Here, we combined genome‐wide CRISPR screening under graded GPX4 inhibition with mechanistic perturbation–rescue experiments and validation in xenograft and immunocompetent syngeneic prostate cancer models. We identified MEPCE loss as a conserved sensitizer to ferroptosis. Mechanistically, MEPCE depletion destabilized RN7SK and disrupted the HEXIM1–P‐TEFb complex, consistent with CDK9 release and enhanced RNA polymerase II Ser2 phosphorylation, thereby promoting transcriptional elongation. This state accelerated activation of a NRF2/ARE stress program encompassing antioxidant defense and iron mobilization. Within this program, HMOX1 emerged as a kinetically sensitive effector whose rapid induction promoted labile iron accumulation and lipid peroxidation under GPX4 inhibition. In vivo, MEPCE suppression impaired tumor growth, enhanced the antitumor efficacy of ferroptosis induction, and was associated with pharmacodynamic markers of ferroptosis that were partially reversed by ferroptosis‐ or iron‐targeted rescue. Together, these findings identify a transcriptional pause‐control mechanism that links elongation dynamics to ferroptosis susceptibility and nominate the MEPCE–RN7SK–P‐TEFb axis as a potential therapeutic target for sensitizing prostate cancer to ferroptosis.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026mepce,
  title = {{Mepce Restrains Ferroptosis in Prostate Cancer Through 7SK–P‐TEFb Pause Control}},
  author = {Tongtong Zhang and Xiangyang Zhan and Jiexiang Zhang and Mingyue Tan and Chuanmin Chu and Guanqun Ju and Xinyu Zhai and Jianyi Gu and Huirong Zhu and Dongliang Xu},
  journal = {Advanced Science},
  year = {2026},
  month = aug,
  doi = {10.1002/advs.76958},
  url = {https://doi.org/10.1002/advs.76958},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Mepce Restrains Ferroptosis in Prostate Cancer Through 7SK–P‐TEFb Pause Control
AU  - Tongtong Zhang
AU  - Xiangyang Zhan
AU  - Jiexiang Zhang
AU  - Mingyue Tan
AU  - Chuanmin Chu
AU  - Guanqun Ju
AU  - Xinyu Zhai
AU  - Jianyi Gu
AU  - Huirong Zhu
AU  - Dongliang Xu
PY  - 2026
DA  - 2026/08/05
JO  - Advanced Science
DO  - 10.1002/advs.76958
UR  - https://doi.org/10.1002/advs.76958
AB  - Ferroptosis can be therapeutically induced through GPX4 inhibition, but the mechanisms that determine ferroptosis sensitivity in prostate cancer remain incompletely understood. Here, we combined genome‐wide CRISPR screening under graded GPX4 inhibition with mechanistic perturbation–rescue experiments and validation in xenograft and immunocompetent syngeneic prostate cancer models. We identified MEPCE loss as a conserved sensitizer to ferroptosis. Mechanistically, MEPCE depletion destabilized RN7SK and disrupted the HEXIM1–P‐TEFb complex, consistent with CDK9 release and enhanced RNA polymerase II Ser2 phosphorylation, thereby promoting transcriptional elongation. This state accelerated activation of a NRF2/ARE stress program encompassing antioxidant defense and iron mobilization. Within this program, HMOX1 emerged as a kinetically sensitive effector whose rapid induction promoted labile iron accumulation and lipid peroxidation under GPX4 inhibition. In vivo, MEPCE suppression impaired tumor growth, enhanced the antitumor efficacy of ferroptosis induction, and was associated with pharmacodynamic markers of ferroptosis that were partially reversed by ferroptosis‐ or iron‐targeted rescue. Together, these findings identify a transcriptional pause‐control mechanism that links elongation dynamics to ferroptosis susceptibility and nominate the MEPCE–RN7SK–P‐TEFb axis as a potential therapeutic target for sensitizing prostate cancer to ferroptosis.
SN  - 2198-3844
ER  -