{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.",
    "Shandong Engineering Laboratory for Urogynecology, Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.",
    "Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Jinan, China.",
    "Department of Obstetrics and Gynecology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.",
    "Department of Clinical Medicine, Medical School of Shandong University, Jinan, China.",
    "Shandong 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.",
    "School of Pharmaceutical Sciences, Tiangong University, Tianjin, China.",
    "Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China. qiluqingzhang@sdu.edu.cn.",
    "Shandong Engineering Laboratory for Urogynecology, Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China. qiluqingzhang@sdu.edu.cn.",
    "Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Jinan, China. qiluqingzhang@sdu.edu.cn.",
    "Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China. yingxinpang@126.com.",
    "Shandong Engineering Laboratory for Urogynecology, Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China. yingxinpang@126.com.",
    "Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Jinan, China. yingxinpang@126.com."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Haocheng Zhang",
      "orcid": "0009-0002-0690-0600"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Zhiling Wang",
      "orcid": "0000-0002-7705-5101"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Xinqin He"
    },
    {
      "affs": [
        4
      ],
      "name": "Yulong Mu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaonan Fan"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Xuan Wei"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Hongluan Mao"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Shuqi Chi"
    },
    {
      "affs": [
        5
      ],
      "name": "Zunling Li"
    },
    {
      "affs": [
        6
      ],
      "name": "Xuehui Pang"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Wei Lu"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Beihua Kong",
      "orcid": "0000-0002-5911-0242"
    },
    {
      "affs": [
        7,
        8,
        9
      ],
      "name": "Qing Zhang",
      "orcid": "0009-0006-4160-9754"
    },
    {
      "affs": [
        10,
        11,
        12
      ],
      "name": "Yingxin Pang",
      "orcid": "0000-0002-1848-757X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6z3h918gs6yf8.bib",
  "cited_by": 0,
  "doi": "10.1038/s41419-026-09125-x",
  "fulltext_url": "https://europepmc.org/articles/PMC13680392",
  "id": "6z3h918gs6yf8",
  "issns": [
    "2041-4889"
  ],
  "landing_url": "https://europepmc.org/article/MED/42897145",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "QH573-671"
    ],
    [
      "openalex",
      "1312|Histone Deacetylase Inhibitors Research"
    ]
  ],
  "openalex": "W7170161463",
  "pdf_url": "https://europepmc.org/articles/PMC13680392?pdf=render",
  "pmcid": "PMC13680392",
  "pmid": "42897145",
  "published": "2026-07-01",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/6z3h918gs6yf8.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:42Z",
      "native_id": "MED:42897145",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42897145"
    },
    {
      "first_seen": "2026-10-30T13:46:35Z",
      "native_id": "afe4bd8f7ede4089bbe5febce7648317",
      "source": "doaj",
      "url": "https://doi.org/10.1038/s41419-026-09125-x"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Histone Deacetylase Inhibitors Research",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Chidamide induces ROS-driven ZAKα-dependent ribotoxic stress in endometrial cancer and enhances radiosensitivity in vitro and in vivo.",
  "title_text": "Chidamide induces ROS-driven ZAKα-dependent ribotoxic stress in endometrial cancer and enhances radiosensitivity in vitro and in vivo.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:46:35Z",
  "url": "https://research.draconitic.com/paper/6z3h918gs6yf8",
  "venue": "Cell death & disease",
  "versions": []
}