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Peer-reviewedCC BYCell death & disease

Chidamide induces ROS-driven ZAKα-dependent ribotoxic stress in endometrial cancer and enhances radiosensitivity in vitro and in vivo.

  • Haocheng Zhang1,2,3
  • Zhiling Wang1,2,3
  • Xinqin He1,4
  • Yulong Mu5
  • Xiaonan Fan1
  • Xuan Wei1,2,3
  • Hongluan Mao1,2,3
  • Shuqi Chi1,2,3
  • Zunling Li6
  • Xuehui Pang7
  • Wei Lu1,2,3
  • Beihua Kong1,2,3
2 more authors
  • Qing Zhang8,9,10
  • Yingxin Pang11,12,13
13 affiliations
  1. 1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.
  2. 2Shandong Engineering Laboratory for Urogynecology, Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.
  3. 3Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Jinan, China.
  4. 4Department of Obstetrics and Gynecology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
  5. 5Department of Clinical Medicine, Medical School of Shandong University, Jinan, China.
  6. 6Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, China.
  7. 7School of Pharmaceutical Sciences, Tiangong University, Tianjin, China.
  8. 8Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China. [email protected].
  9. 9Shandong Engineering Laboratory for Urogynecology, Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China. [email protected].
  10. 10Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Jinan, China. [email protected].
  11. 11Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China. [email protected].
  12. 12Shandong Engineering Laboratory for Urogynecology, Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China. [email protected].
  13. 13Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Jinan, China. [email protected].
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Abstract

Chidamide is a selective histone deacetylase inhibitor with antitumor activity in several malignancies, but its mechanism of action in endometrial cancer (EC) remains poorly understood. In this study, we investigated the cytotoxic effects and underlying mechanism of chidamide in EC using cell lines, patient-derived organoids (PDOs), cell-derived xenograft (CDX) models, and patient-derived xenograft (PDX) models. Chidamide markedly inhibited EC cell growth and induced reactive oxygen species (ROS) accumulation, DNA damage, G2/M-phase arrest, and apoptosis. Mechanistically, transcriptomic and functional analyses showed that chidamide disrupted translational homeostasis and activated a ROS-dependent, ZAKα-mediated ribotoxic stress response, leading to p38 and JNK activation. Scavenging ROS with N-acetylcysteine (NAC) attenuated ZAKα-MAPK signaling, and partially rescued chidamide-induced cell cycle arrest and apoptosis. Similarly, pharmacological ZAK inhibition or ZAKα silencing weakened stress signaling and diminished the cytotoxic effects of chidamide, supporting the central role of the ROS-ZAKα-MAPK axis. Chidamide also activated the GCN2-eIF2α-ATF4 integrated stress response, and ISRIB further enhanced stress signaling and apoptosis, suggesting an adaptive buffering role of this pathway. In addition to its activity in vitro, chidamide showed broad antitumor efficacy in PDO, CDX, and PDX models. Chidamide also enhanced tumor radiosensitivity in vivo, supporting its potential utility in combination with radiotherapy. Together, these findings identify ROS-driven, ZAKα-dependent ribotoxic stress signaling as a key mechanism underlying chidamide-induced cytotoxicity in EC and provide a mechanistic rationale for the further development of chidamide-based strategies in this disease.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026chidamide,
  title = {{Chidamide induces ROS-driven ZAKα-dependent ribotoxic stress in endometrial cancer and enhances radiosensitivity in vitro and in vivo.}},
  author = {Haocheng Zhang and Zhiling Wang and Xinqin He and Yulong Mu and Xiaonan Fan and Xuan Wei and Hongluan Mao and Shuqi Chi and Zunling Li and Xuehui Pang and Wei Lu and Beihua Kong and Qing Zhang and Yingxin Pang},
  journal = {Cell death \& disease},
  year = {2026},
  month = jul,
  doi = {10.1038/s41419-026-09125-x},
  url = {https://europepmc.org/article/MED/42897145},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Chidamide induces ROS-driven ZAKα-dependent ribotoxic stress in endometrial cancer and enhances radiosensitivity in vitro and in vivo.
AU  - Haocheng Zhang
AU  - Zhiling Wang
AU  - Xinqin He
AU  - Yulong Mu
AU  - Xiaonan Fan
AU  - Xuan Wei
AU  - Hongluan Mao
AU  - Shuqi Chi
AU  - Zunling Li
AU  - Xuehui Pang
AU  - Wei Lu
AU  - Beihua Kong
AU  - Qing Zhang
AU  - Yingxin Pang
PY  - 2026
DA  - 2026/07/01
JO  - Cell death & disease
DO  - 10.1038/s41419-026-09125-x
UR  - https://europepmc.org/article/MED/42897145
AB  - Chidamide is a selective histone deacetylase inhibitor with antitumor activity in several malignancies, but its mechanism of action in endometrial cancer (EC) remains poorly understood. In this study, we investigated the cytotoxic effects and underlying mechanism of chidamide in EC using cell lines, patient-derived organoids (PDOs), cell-derived xenograft (CDX) models, and patient-derived xenograft (PDX) models. Chidamide markedly inhibited EC cell growth and induced reactive oxygen species (ROS) accumulation, DNA damage, G2/M-phase arrest, and apoptosis. Mechanistically, transcriptomic and functional analyses showed that chidamide disrupted translational homeostasis and activated a ROS-dependent, ZAKα-mediated ribotoxic stress response, leading to p38 and JNK activation. Scavenging ROS with N-acetylcysteine (NAC) attenuated ZAKα-MAPK signaling, and partially rescued chidamide-induced cell cycle arrest and apoptosis. Similarly, pharmacological ZAK inhibition or ZAKα silencing weakened stress signaling and diminished the cytotoxic effects of chidamide, supporting the central role of the ROS-ZAKα-MAPK axis. Chidamide also activated the GCN2-eIF2α-ATF4 integrated stress response, and ISRIB further enhanced stress signaling and apoptosis, suggesting an adaptive buffering role of this pathway. In addition to its activity in vitro, chidamide showed broad antitumor efficacy in PDO, CDX, and PDX models. Chidamide also enhanced tumor radiosensitivity in vivo, supporting its potential utility in combination with radiotherapy. Together, these findings identify ROS-driven, ZAKα-dependent ribotoxic stress signaling as a key mechanism underlying chidamide-induced cytotoxicity in EC and provide a mechanistic rationale for the further development of chidamide-based strategies in this disease.
SN  - 2041-4889
ER  -