The KAT8-CDK1 K33 acetylation axis drives doxorubicin resistance by suppressing ferroptosis and apoptosis in breast cancerDownload PDF Download PDF ArticleOpen accessPublished: 03 August 2026Qingzhi Zhao1 na1,Qixian Zou1 na1,Jinmeng Chu1,Yizhen Wang1,Tiantian Xu1,Haoqing Dou1,Chengyu Cai1,Na Zhang1,Fei Wang1,Yin Gao1,Yong Cai1,Bing Liang ORCID: orcid.org/0000-0002-0048-93072 &…Jingji Jin ORCID: orcid.org/0000-0001-9432-59541 Cell Death & Disease (2026) Cite this articleSave articleView saved research We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.AbstractDoxorubicin (Dox) resistance severely limits therapeutic efficacy in breast cancer, yet the epigenetic mechanisms linking cell-cycle control to therapy-induced cell death remain unclear. Here, we identify the histone acetyltransferase KAT8 as a critical driver of Dox resistance. Transcriptomic analysis of neoadjuvant cohorts revealed elevated KAT8 expression in residual disease (RD) tumors, which was validated in an independent cohort of 95 patients. High KAT8 levels correlated with poor therapeutic response. Mechanistically, KAT8 directly acetylated CDK1 at lysine 33 (K33) in Dox-resistant MCF-7/ADR and MDA-MB-231/ADR cells. K33 acetylation sustained CDK1 phosphorylation at T14, Y15, and T161, maintaining kinase activity under chemotherapeutic stress. Disruption of KAT8, either by genetic silencing or pharmacological inhibition with MG149, reduced CDK1 activation, increased mitochondrial depolarization and oxidative stress, and restored Dox sensitivity. Functionally, KAT8-dependent CDK1 K33 acetylation suppressed both apoptosis and ferroptosis, two principal Dox-induced cell death pathways. Re-expression of wild-type CDK1, but not the acetylation-deficient K33R mutant, rescued chemoresistance. In vivo, MG149 co-treatment or expression of CDK1-K33R significantly enhanced Dox-mediated tumor suppression in xenograft models without overt toxicity. Together, these findings establish KAT8-dependent CDK1 K33 acetylation as a key epigenetic mechanism sustaining anthracycline resistance and suggest that targeting the KAT8-CDK1 axis may provide a therapeutic strategy to overcome refractory breast cancer.SubjectsBreast cancerEpigeneticsAcknowledgementsWe thank the Department of Biobank, Division of Clinical Research, The First Hospital of Jilin University for providing the human tissue specimens.FundingThis work was supported by the National Natural Science Foundation of China (No. 32170599, JJ), and Jilin Provincial Science and Technology Development Plan project (20240404042ZP, BL). The funders had no role in study design, data collection and analysis, publication decisions, or manuscript preparation.Author informationAuthor notesThese authors contributed equally: Qingzhi Zhao, Qixian Zou.Authors and AffiliationsSchool of Life Sciences, Jilin University, Changchun, ChinaQingzhi Zhao, Qixian Zou, Jinmeng Chu, Yizhen Wang, Tiantian Xu, Haoqing Dou, Chengyu Cai, Na Zhang, Fei Wang, Yin Gao, Yong Cai & Jingji JinSchool of Nursing, Jilin University, Changchun City, ChinaBing LiangAuthorsQingzhi ZhaoView author publicationsSearch author on:PubMed Google ScholarQixian ZouView author publicationsSearch author on:PubMed Google ScholarJinmeng ChuView author publicationsSearch author on:PubMed Google ScholarYizhen WangView author publicationsSearch author on:PubMed Google ScholarTiantian XuView author publicationsSearch author on:PubMed Google ScholarHaoqing DouView author publicationsSearch author on:PubMed Google ScholarChengyu CaiView author publicationsSearch author on:PubMed Google ScholarNa ZhangView author publicationsSearch author on:PubMed Google ScholarFei WangView author publicationsSearch author on:PubMed Google ScholarYin GaoView author publicationsSearch author on:PubMed Google ScholarYong CaiView author publicationsSearch author on:PubMed Google ScholarBing LiangView author publicationsSearch author on:PubMed Google ScholarJingji JinView author publicationsSearch author on:PubMed Google ScholarCorresponding authorsCorrespondence to Yong Cai, Bing Liang or Jingji Jin.Ethics declarationsCompeting interestsThe authors declare no competing interests.Ethics approval and consent to participateThis study was conducted in compliance with the principles of the Declaration of Helsinki. Informed consent was obtained from all subjects. Ethical approval for human subjects was provided by the Ethics Committee of the First Hospital of Jilin University (Approval No. 2023-395).Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Edited by Dr Lujun ChenSupplementary informationRights and permissionsOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Reprints and permissionsAbout this articleDownload PDF